1) The course of disease in HPS may be either a short-term mild process or a rapidly fatal disease. A prodromal phase generally lasts 3 to 6 days. It is characterized by a flu-like illness with fever, headache, myalgias, and often gastrointestinal disturbances. Respiratory symptoms are often initially absent in adults but not in children. Physical examination, laboratory tests, and chest films may be normal. Since symptoms are nonspecific, diagnosis can be very difficult. The cardiopulmonary phase starts with a progressive cough and dyspnea accompanied by tachypnea, tachycardia, fever, and hypotension. Progressive hypoxemia requiring intubation and mechanical ventilation is common. Intractable hypotension leading to fatal cardiac dysrhythmias may occur. Survivors of the cardiopulmonary phase may undergo a convalescent phase, which is marked by improved oxygenation and hemodynamic function and no apparent long-term sequelae. However, fatality rates have occurred in over a third of reported cases.

1) Treatment is primarily symptomatic and supportive. Treat patients with fever with antipyretics (eg, acetaminophen, ibuprofen). Treat myalgias with standard nonsteroidal antiinflammatories. Gastrointestinal symptoms can be treated with antiemetics or fluid hydration as needed. Despite a lack of reports of human to human transmission, respiratory isolation of HPS patients is advised with caregivers wearing particle masks.

1) Treatment is primarily symptomatic and supportive. Patients in the cardiopulmonary phase should be aggressively treated. Respiratory distress may require intubation and mechanical ventilation with advanced ventilation settings. Hypotension can be treated with intravenous fluids and pressors as needed. Because of the likely role of capillary leak in pathogenesis, fluids should be given cautiously if HPS is suspected. More invasive treatments such as extracorporeal membrane oxygenation can be used for patients in severe cardiopulmonary distress. Broad spectrum antibiotics should be given to patients who develop sepsis. Ribavirin has been used in patients with HPS; however, there is a lack of evidence for its efficacy. Other experimental treatments include bradykinin antagonists and nitric oxide.

1) PREHOSPITAL: There is no evidence for prehospital decontamination to prevent HPS.
2) HOSPITAL: There is no evidence for the use of activated charcoal, gastric lavage, or whole bowel irrigation for HPS.

1) Patients who enter the cardiopulmonary phase of illness are likely to require airway management and may decompensate quickly. Therefore, once respiratory symptoms start, close monitoring of intubation and mechanical ventilation should occur.

1) None.

1) OBSERVATION CRITERIA: Anyone with suspected HPS should be sent to a healthcare facility for observation. Patients may be discharged once they are clearly improving and have no respiratory symptoms. They should be instructed to return quickly if they develop any respiratory symptoms.
2) ADMISSION CRITERIA: Any patients with respiratory symptoms should be admitted to the hospital and likely to an intensive care unit because of the risk of developing severe disease. All patients should remain in the hospital until they are clearly improving and recovered from any cardiopulmonary symptoms.
3) CONSULT CRITERIA: All cases should be reported to the local health department and the Centers for Disease Control (CDC Hantavirus Hotline: (877) 232-3322 or (404) 639-1510). Consider consultation with infectious disease specialists and pulmonologists/intensivists. Poison centers that communicate with public health departments may help with notifications and for providing information to the general public.

1) One common pitfall is missing the diagnosis when it appears in the prodromal phase and not recognizing the exposure to rodents as a risk factor. Another pitfall is the rapidity of the severity of disease once patients have respiratory symptoms.

1) Since hantaviruses are spread through rodent droppings, people who may have exposure to rodents (especially in areas where it is known to be endemic, such as the Sin Nombre virus in deer mice in the Four Corners region of the United States) are at highest risk.

1) HPS can look like many other viral syndromes (eg, influenza virus, arenavirus) or causes of ARDS.

1) HPS is an acute respiratory illness characterized by a febrile prodrome, followed by rapid development of acute respiratory distress (CDC, 1993) 1993j; (Duchin et al, 1994).
2) Respiratory symptoms often are absent initially. Tachypnea occurs during subsequent cardiopulmonary stage and often may be noted before rales and chest film abnormalities are detected (Butler & Peters, 1994).

1) Onset of illness is characterized by a flu-like prodrome consisting of fever (T >/=38.3 C) accompanied by myalgias and variable respiratory symptoms. Fever is present in almost all cases and continues throughout the hospital course (CDC, 1993j; Duchin et al, 1994; Levy & Simpson, 1994; Butler & Peters, 1994; Khan et al, 1996b; Courouble et al, 2001). In a case series of 13 children with hantavirus, 100% were reported with fever as a prodromal symptom (Ramos et al, 2001).
2) Chills are present during flu-like prodrome in about 2/3 of cases (Duchin et al, 1994).

1) About 50% of patients develop hypotension during their hospital course. It typically is accompanied by fever and hypoxia; however, hypotension does not appear to be a direct consequence of hypoxia, since some patients with adequate oxygenation have progressive hypotension (Duchin et al, 1994; Butler & Peters, 1994; CDC, 1993j).

1) Increased pulse rate is a common finding during the cardiopulmonary phase (Dara et al, 2005; Butler & Peters, 1994).

1) Upper respiratory tract manifestations such as sore throat, pharyngeal injection or exudate, earache, conjunctivitis, and rhinorrhea are UNUSUAL in patients with HPS and suggest another diagnosis (Duchin et al, 1994; Dull et al, 1994; Butler & Peters, 1994).
2) Following the prodromal phase, a cardiopulmonary phase occurs, generally heralded by progressive cough and shortness of breath. Cough is present in about 75% of cases (CDC, 1993j; Duchin et al, 1994; Levy & Simpson, 1994; Butler & Peters, 1994).

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1) Several case reports have been published of acute Sin Nombre hantavirus (SNV) infection without a pulmonary syndrome. These patients had characteristic prodromal symptoms but did not progress to severe pulmonary involvement. These cases are atypical and do not meet the clinical criteria for HPS, although they were confirmed as acute SNV infections with substantial titers of anti-SNV IgM and either substantial acute-phase titers of IgG or a fourfold rise in convalescent-phase IgG titers. It is unclear why the hallmark of HPS (cardiopulmonary symptoms) did not develop in these patients (Kitsutani et al, 1999; Zavasky et al, 1999).

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1) In a case review of 5 women with documented HPS during pregnancy (gestational age ranging from 13 to 29 weeks), one maternal death and 2 fetal deaths in utero resulted. Autopsies of the 2 fetuses and 3 placentas revealed no sign of transplacental hantavirus transmission. None of the 3 surviving newborns showed serological evidence of conversion. Vertical transmission via a transplacental route was not evident (Howard et al, 1999).

1) HPS occurring during pregnancy may be life-threatening and may result in fetal hypoxic damage, even with early diagnosis and intensive respiratory support of the mother (Gilson et al, 1994).
2) The high oxygen demands of pregnancy are unable to be matched by oxygen delivery in ARDS and may predispose the mother to multiple organ failure, as well as fetal oxygen deprivation. The patient's oxygen requirement decreases dramatically after delivery (Gilson et al, 1994).
3) HPS should be suspected in a previously healthy obstetric patient who has acute respiratory distress or ARDS accompanying what appears to be an "atypical" or viral pneumonia (Gilson et al, 1994).
4) Prompt delivery may be associated with an improved maternal and fetal outcome if maternal hypoxia or lactic acidemia, or both, are present (Gilson et al, 1994).
5) A case of possible transfer of passive antibodies from mother to fetus (without fetal infection) has been reported (Pini et al, 1998).

1) In a case of a mother who had been breast-feeding her 3-week-old infant prior to discovery she was infected with Sin Nombre hantavirus (SNV), it was reported that neither SNV RNA nor antibodies were found in the infant's blood. The presence of SNV RNA as well as neutralizing antibodies was found during an analysis of the mother's blood and breast milk. Perinatal transmission did not occur in this case, even though breast-feeding occurred during the incubation period of hantavirus cardiopulmonary syndrome (Pai et al, 1999).

1) Complete blood count is the most striking and diagnostically helpful laboratory test (Levy & Simpson, 1994; Dull et al, 1994; Butler & Peters, 1994).
2) INCREASED HEMATOCRIT: Hemoconcentration is a characteristic laboratory finding, indicating capillary leak; noted on admission in 75% of patients (CDC, 1993j; Duchin et al, 1994; Levy & Simpson, 1994). In one series, hematocrit was >50% in men and >45% in women (Duchin et al, 1994).
3) WHITE BLOOD CELLS INCREASED: CBC is most striking and diagnostically helpful laboratory test. Peripheral smear showing triad of leukocytosis with a left shift in myeloid series, large immunoblastic lymphocytes, and thrombocytopenia on initial presentation (before hypoxia occurs) is unique and characteristic for HPS (Levy & Simpson, 1994; Dull et al, 1994; Duchin et al, 1994; CDC, 1994b).
4) WHITE BLOOD CELLS, DECREASED: Some patients with HPS may present with leukopenia (WBC less than 4000/mm(3)) (CDC, 1994b).
5) PLATELETS DECREASED: Decreased platelet count is a characteristic laboratory abnormality; noted on admission in 70% of patients (CDC, 1993j) and in 100% of 13 children in a case series (Ramos et al, 2001). Median lowest platelet count is 64,000/mm(3) (Duchin et al, 1994) and 67,000/mm(3) in children (Ramos et al, 2001).
6) PROLONGED THROMBOPLASTIN TIME is a common finding (Duchin et al, 1994).
7) ELEVATED PT: In a case series of 13 children with HPS, an elevated prothrombin time (> or = 14 seconds) at hospital admission was prognostic of mortality (Ramos et al, 2001).
8) Following the onset of noncardiogenic pulmonary edema detected by radiographic studies, the presence of 4 of the 5 findings (thrombocytopenia, myelocytosis, hemoconcentration, lack of significant toxic granulation in neutrophils, and more than 10% of lymphocytes with immunoblastic morphologic features) has a specificity of 99% for patients with hantavirus cardiopulmonary syndrome (Koster et al, 2001).

1) Lactic acid levels may be elevated on admission and become elevated at some point during the hospital course in a majority of cases (Duchin et al, 1994; Levy & Simpson, 1994).
2) Serum hepatic enzyme levels typically are mildly elevated at time of admission and increase during the hospital course (Duchin et al, 1994; Levy & Simpson, 1994). In a case series of 13 children, 100% were shown to have elevated lactate dehydrogenase (median level, 1243 IU/L) on hospital admission (Ramos et al, 2001).

1) Mild-to-moderate proteinuria often is present, but frank renal failure is not a feature in most cases (Butler & Peters, 1994).

1) OXYGEN SATURATION
2) ULTRASOUND
3) ECG

a) Findings may be normal in prodromal phase and initially in patients hospitalized with HPS (Ketai et al, 1994).
b) HPS causes an atypical form of increased permeability pulmonary edema; findings differ from those usually seen in ARDS/non-cardiogenic pulmonary edema. Changes are similar to those of cardiogenic pulmonary edema but without the other radiographic or clinical stigmata of pulmonary venous hypertension (Ketai et al, 1994).
c) Characterized initially by findings of capillary leak syndrome: prominent interstitial edema (due to endothelial leakage with relative sparing of alveolar epithelium), seen on chest films as hazy bilateral lower lobe pulmonary infiltrates. These findings develop within 2 days of hospitalization (CDC, 1993j; Duchin et al, 1994; Levy & Simpson, 1994; Dull et al, 1994; Ketai et al, 1994).
d) Early, prominent interstitial edema and nonperipheral distribution of initial air space disease are uncommon among patients with ARDS and may be useful in identifying patients with HPS. If extensive, these findings are associated with high mortality (Ketai et al, 1994).
e) Pleural effusions, indistinct hilum, Kerley B lines, and bronchial cuffing also may develop; cardiomegaly is not seen (Sankaranarayanan et al, 2003; Ketai et al, 1994).
f) Findings indicative of interstitial edema are present more often than is typically seen in ARDS (88% vs 5% of cases). Alveolar flooding subsequently develops in most patients and is not the peripheral pattern usually seen in the acute phase of ARDS (i.e., it tends to be basilar or perihilar rather than peripheral) (Ketai et al, 1994).
g) It is postulated that intact alveolar epithelium slows the earliest phases of alveolar flooding, which may affect the distribution of air space disease, altering initial peripheral distribution seen in typical ARDS (Ketai et al, 1994).
h) Intact alveolar membrane also may maintain a greater portion of the extracellular lung water within the interstitium. This would account for the greater prominence of Kerley B lines and peribronchial cuffing than is typically seen on chest films in patients with ARDS (Ketai et al, 1994).

A) SUMMARY: Any patients with respiratory symptoms should be admitted to the hospital and likely to an intensive care unit because of the risk of developing severe disease. All patients should remain in the hospital until they are clearly improving and recovered from any cardiopulmonary symptoms.
B) Admission is indicated for all patients with suspected HPS in whom O2 saturation is abnormal, whether or not the CBC is normal or characteristic of HPS (Dull et al, 1994).
C) Since there is currently no specific therapy for HPS, early diagnosis and supportive care in an intensive care setting, with prompt correction of electrolyte, pulmonary, and hemodynamic abnormalities, remain cornerstones of therapy, especially since the patient's condition may deteriorate quickly (Khan et al, 1996b). Immediate transfer of patients to a facility with an ICU experienced in the management of sepsis is essential (Hallin et al, 1996).

A) All cases should be reported to the local health department and the Centers for Disease Control (CDC Hantavirus Hotline: (877) 232-3322 or (404) 639-1510). Consider consultation with infectious disease specialists and pulmonologists/intensivists. Poison centers that communicate with public health departments may help with notifications and for providing information to the general public.

A) Immediate transfer of patients to a facility with an ICU experienced in the management of sepsis is essential (Hallin et al, 1996). Improving survival may be related to availability of more sophisticated care and possibly access to salvage therapy (Levy & Simpson, 1994; Dull et al, 1994).

A) Anyone with suspected HPS should be sent to a healthcare facility for observation. Patients may be discharged once they are clearly improving and have no respiratory symptoms. They should be instructed to return quickly if they develop any respiratory symptoms.

1) MANAGEMENT OF MILD TO MODERATE TOXICITY
2) MANAGEMENTS OF SEVERE TOXICITY

1) Hantavirus cases can be confirmed via serology, immunohistochemistry, or polymerase chain reaction studies.
2) A complete blood count (CBC) is the most useful initial test. A classic triad of thrombocytopenia, leukocytosis with a left shift in myeloid series, and large immunoblastic lymphocytes on initial presentation may appear on the peripheral smear and is characteristic for HPS. Hemoconcentration and thrombocytopenia may appear in up to 3/4 of patients. Some patients with HPS may present with leukopenia.
3) Other laboratory findings include elevated serum lactate levels (especially once patients develop hypoxia or hypotension), prolonged PT and PTT times, proteinuria, hypoalbuminemia, and elevated serum lactate dehydrogenase concentration.
4) Obtain an ECG, and institute continuous cardiac monitoring.
5) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests in any patient with respiratory symptoms. A chest x-ray is required in all patients with HPS.

1) Patients who enter the cardiopulmonary phase of illness are likely to require airway management and may decompensate quickly. Therefore, once respiratory symptoms start, close monitoring of intubation and mechanical ventilation should occur.
2) Respiratory distress and hypoxemia may be treated initially with oxygen via cannula (4 to 6 L/min).

1) SUMMARY
2) Because of the likely role of capillary leak in pathogenesis, fluids should be given cautiously if HPS is suspected. Avoid volume expansion and overhydration (Duchin et al, 1994).
3) DOPAMINE
4) NOREPINEPHRINE

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
8) Extracorporeal membrane oxygenation (ECMO) may provide short-term benefit for patients with circulatory failure and advanced pulmonary capillary leak syndrome, with dramatic evidence of hemodynamic stabilization within 12 to 24 hours of implementation (Pickering et al, 2003).

1) All patients with suspected HPS must be treated presumptively for sepsis with antibiotics that will treat the usual causes of infection. Specific choices depend on patient's presentation; should include plague coverage.
2) ANTIVIRALS: Ribavirin has no clearly positive influence on outcome and is no longer recommended or available under CDC protocol. Ribavirin was available as an investigational agent through a CDC-sponsored open label protocol for patients with HPS. Although the drug was generally well tolerated, it had no clearly positive influence on outcome. As a result, enrollment under this protocol has been closed and its role in treatment of HPS remains to be defined (CDC, 1994b).

1) Person-to-person or nosocomial transmission of HPS has not been documented and is unlikely to occur in health care settings (Vitek et al, 1994). However, standard precautions and respiratory isolation of all suspected cases is advised, since the infection is thought to be contracted by inhalation of infectious particles (Levy & Simpson, 1994; Butler & Peters, 1994; Vitek et al, 1996).
2) Particle masks are required for all persons entering the room; outside venting rooms are recommended but not required. Once patients have clinical remission, they may be transferred to private rooms where standard precautions are maintained (Levy & Simpson, 1994).

1) RBCs are indicated to maintain O2 delivery if hemoglobin level decreases (Levy & Simpson, 1994).
2) Platelet transfusions are not required to treat thrombocytopenia, as this laboratory finding mirrors the clinical course (Levy & Simpson, 1994).

1) BRADYKININ ANTAGONISTS
2) NITRIC OXIDE

a) Laboratory values included hematocrit of 49.6%, platelet count of 195,000/mm(3), WBC count of 7100/mm(3) (66% segmented neutrophils and 10% band forms), and serum LDH was 195 International Units/L (normal, 100 to 190 International Units/L). The patient was discharged. His symptoms persisted, and 2 days later he was re-admitted with vomiting and diarrhea. At this time blood pressure was 90/70 mmHg and temperature was 36 degrees C. Physical examination was normal, and he was again discharged.
b) Shortly following the second discharge, a cough with copious yellow sputum, sometimes blood-tinged, and progressive dyspnea developed. The patient died the day after discharge following an acute respiratory failure and cardiopulmonary arrest.
c) At the time of death his WBC count was 65,300/mm(3), with 45% segmented neutrophils and 27% band forms. Hematocrit had risen to 60.2% and platelet count was 42,000/mm(3). Other laboratory values included serum creatinine of 2.5 mg/dL (220 mcmol/L), BUN of 32 mg/dL (11.4 mmol/L), LDH of 1486 International Units/L, and creatine kinase of 814 Units/L with an MB fraction of 87 Units/L (11%). Diffuse interstitial and alveolar infiltrates were seen on chest radiograph. Following necropsy, hantavirus pulmonary syndrome was diagnosed (Duchin et al, 1994).

a) Accurate predictors of mortality have been the following combinations of maximally elevated laboratory values: (1) hematocrit and lactate dehydrogenase level (P < 0.005), (2) the hematocrit and partial-thromboplastin time (P < 0.002), and (3) white-cell count and partial-thromboplastin time (P < 0.002) (Duchin et al, 1994).