Hantavirus--english

7. CLINICAL MANIFESTATIONS AND TREATMENT OF
HANTAVIRUS PULMONARY SYNDROME (61)
INCUBATION PERIOD
ings of pleural effusion. Cough, tachypnea, and exertionaldyspnea are not reported at the onset of the prodrome, Few cases have had clearly defined exposures in time but appear later and herald the onset of pulmonary and place. The incubation period of other hantavirus diseases is typically one to four weeks, although HFRS The onset of hypotension and pulmonary edema may from Hantaan virus has apparently had an incubation progress rapidly over the course of 4 to 24 hours. A res- period up to six weeks. In an effort to determine the in- piratory rate of 24/min is a sensitive but not specific in- cubation period of HPS-causing viruses in the United dicator of early pulmonary edema in HPS. Early pulmo- States, eight cases were identified with well-defined and nary edema is imaged on the chest X-ray as Kerley B isolated exposures. These findings suggested an incuba- lines, peribronchial cuffing, and alveolar-interstitial fluid tion period ranging from 9 to 35 days from the time of in the basal segments (64). At this point, hypoxemia be- probable infection to onset of symptoms (J. Young, per- comes apparent, with an oxygen saturation of hemoglo- sonal communication). For seven of the eight cases re- bin less than 95% at sea level and less than 90% at viewed, the incubation period was within 9 to 24 days.
2,000 m or more above sea level. Pulmonary edema isnoncardiogenic in origin, as indicated by normal pul-monary capillary wedge pressures obtained through aSwan-Ganz catheter and normal heart size on the X-ray CLINICAL MANIFESTATIONS
(65, 66). Markedly increased pulmonary capillary per-meability results in high-protein pulmonary edema; se- Following aerosol exposure and deposition of the vi- verely ill patients may require up to 1 L/h of serum- rus deep in the lung, infection is initiated. A viremic pe- resembling fluid to be removed from their airways by riod ensues, with extensive pulmonary endothelial in- suction. Shock may be manifest as hypotension and is fection. The onset of symptoms coincides with the onset often accompanied by oliguria and delirium. Hypo- of the immune response, which may reduce virus shed- volemia resulting from a shift in fluid from circulating ding, suggesting that the disease process itself is immu- blood to the lung interstitium and air spaces contributes to the fall in blood pressure. However, most patients also The disease is divided into four phases: febrile, car- experience a serious depression of the myocardium (65).
diopulmonary, diuretic, and convalescent phases (62).
Seriously ill patients may have cardiac indices less than The febrile, or prodromal, phase typically lasts 3 to 5 days (range 1–12 days) and is indistinguishable from other Spontaneous diuresis indicates the onset of the diuretic viral prodromes (63). This phase is characterized by fe- phase. This third phase of the disease is characterized ver, myalgias, chills, asthenia, dizziness, headache, an- by a rapid clearance of the pulmonary edema fluid, reso- orexia, nausea with or without vomiting, abdominal pain, lution of fever, and shock. Convalescence extends over and diarrhea. The abdominal pain may be sufficiently the next two weeks to two months. Patients appear to severe to mimic appendicitis or pyelonephritis. While recover fully, but formal studies of pulmonary function conjunctival suffusion is rarely seen in HPS in North and other clinical parameters are needed.
America, facial flushing is commonly seen in HPS cases In South America, some other clinical aspects have in the Patagonian region of South America. Indications been described, including hemorrhagic complications of upper respiratory tract disease, including sore throat, (i.e., petechias, not observed in North America) and re- rhinorrhea, sinusitis, and ear pain, are usually absent.
nal manifestations (46). As well, HPS has appeared in Physical examination may or may not reveal rales or find- children, an uncommon finding in North America (40).
CLINICAL LABORATORY FINDINGS
iting, and abdominal pain should raise the index of sus-picion and prompt the clinician to inquire about poten- Hematologic findings can be striking in HPS cases (62, tial rodent exposures. Tachypnea is an important sign, 67). In SNV infection, the white blood cell count can be and hypotension may be present. The absence of certain normal or elevated on admission (median 10,400 mm3; signs and symptoms can help to distinguish HPS from range 3,100–65,300 mm3) and usually increases, often other acute viral syndromes: rash, conjunctivitis, sinusi- to very high values (median of maximum values 26,000 tis, otitis, rhinorrhea, exudative pharyngitis, and arthritis mm3 with range 5,600–65,300 mm3). Similar values have are notably rare in HPS (63). Initial laboratory workup in been found with other viruses. There is an absolute neu- suspected cases should include pulse oximetry, chest trophilia and a relative lymphopenia. In addition to im- radiograph, and a complete blood count. The likelihood mature “band” forms, the blood almost always contains of HPS is high in those with a compatible clinical history the more undifferentiated forms in the myeloid series, plus an oxygen saturation measurement of less than 90%, the myelocytes, and promyelocytes. Among the circu- interstitial infiltrates or other indications of pulmonary lating lymphocytes are prominent mononuclear cells with edema on chest X-ray, and thrombocytopenia, particu- deep blue cytoplasm by Giemsa stain and that measure larly if the last is accompanied by left-shifted leukocyto- greater than 18 µ in diameter. These immunoblasts are seen in few infections other than HPS and HFRS, and At the onset of pulmonary edema, almost every case appear in the circulation coincident with the onset of displays thrombocytopenia, left-shifted myeloid series, pulmonary edema. Thrombocytopenia with a platelet and immunoblasts. This hematologic diagnostic triad is count less than 150,000/mm3 is seen in almost every case sufficiently sensitive and specific to use to initiate trans- and, in rare cases, may fall to 20,000/mm3. Thrombocy- fer to intensive care and treatment (see Section 7.6). Prior topenia is the first abnormality to appear in the periph- to the onset of the signs and symptoms of either shock or eral blood, often two or three days before the onset of pulmonary edema, the diagnostic triad is not present on pulmonary edema, and may be used to screen undiffer- the peripheral blood smear. Therefore, to raise the sus- entiated fevers for HPS when the appropriate epidemio- picion of impending HPS, the clinician must use the com- logic clues are elicited by history.
bination of three factors: epidemiologic clues to poten- Elevated creatinine and blood urea nitrogen reflect the tial exposure, the reported findings of fever and myalgias, degree of shock and hypovolemia. Proteinuria may be and thrombocytopenia. Although fully developed HPS seen and microscopic hematuria is found in most cases.
is a characteristic disease, no combination of symptoms Patients infected by Bayou, Black Creek Canal, and Andes is sufficiently sensitive or specific to distinguish its early viruses may have more prominent renal failure, even re- stages from a host of other pulmonary infections (63); quiring hemodialysis (17, 45, 68, and Lázaro, personal this requires the clinician to retain a level of suspicion communication). Elevated hepatic enzymes are seen in until HPS is ruled out. When sufficient evidence for HPS all cases, but rarely attain a level greater than five times has accumulated, the patient should be transported im- the upper normal limit, and hyperbilirubinemia is not seen.
mediately to a unit skilled in intensive cardiopulmonary The multiorgan failure common in sepsis or posttraumatic care, as rapid transport can be lifesaving. However, the adult respiratory distress syndrome (ARDS) rarely occurs decision to move the patient must be weighed against in HPS. Specific pathology of these organ systems has not the rapid onset of hypoxemia and the local capabilities yet been described with any of the HPS viruses, but expe- for medical evaluation. In all areas with previously known rience and surveillance definitions are limited.
or suspected cases of HPS, active clinical investigation In contrast to HFRS, the coagulopathy of HPS is usu- to definitively diagnose HPS should be performed in all ally subclinical. Almost all patients have evidence of persons with unexplained febrile syndrome and epide- coagulopathy but with elevated partial thromboplastin miologic risk factors (see Figure 2).
times. Circulating D-dimers are not common, and fibrino-gen levels falling below 200 mg/dl are rare.
DIFFERENTIAL DIAGNOSIS
EARLY CASE RECOGNITION
The differential diagnosis is extensive prior to the sero- logic identification of hantavirus infection. Most com- Clinicians should consider HPS in patients with fever monly encountered are bilateral pneumonia with sepsis, and myalgias, particularly of the larger muscle groups, adult respiratory distress syndrome complicating systemic including shoulders, thighs, and lower back. The addi- infections, trauma and other life-threatening conditions, tion of such gastrointestinal complaints as nausea, vom- and sepsis syndrome complicated by either disseminated FIGURE 2. Hantavirus pulmonary syndrome algorithm.
• Oxygen saturation <90, or
with or without left-shiftedleukocytosis and elevated hematocrit, • Interstitial or bilateral pattern in X-ray • Hospitalization• Etiological studies intravascular coagulation (DIC) or alcohol toxicity. A (Junin, Machupo, Sabia, and Guanarito viruses). When variety of enzootic infections encountered in rural areas abdominal or back pain is severe, possible diagnoses of of North America may be confused initially with HPS, pyelonephritis, appendicitis, abdominal abscess, or gy- particularly when thrombocytopenia is present. These necological infection should be considered.
include plague, tularemia, Rocky Mountain spotted fe-ver or murine typhus, granulocytic or monocytic ehrli-chiosis, leptospirosis, relapsing fever due to Borrelia LABORATORY DIAGNOSIS
hermsii, and acute parvovirus infection. In Latin America,other diagnostic possibilities would include dengue fe- The most practical approach for the laboratory diag- ver, dengue hemorrhagic fever, and arenavirus infections nosis of hantavirus infection in humans is the detection of IgM antibodies in acute serum samples using an ELISA At postmortem the lungs are massively edematous, but IgM capture assay. Virtually all confirmed HPS patients microscopic studies find little necrosis. There are scant to have demonstrable IgM in the first or second serum moderate hyaline membranes, intact pneumocytes, and sample taken after hospitalization. And while ELISA tests scarce neutrophils (67). However, there is interstitial infil- to detect IgG antibodies may also be used to confirm tration by T lymphocytes and activated macrophages (72).
diagnosis, two serum samples taken two to three weeks These findings differ from those of typical adult respira- apart are required to demonstrate rising titers of IgG an- tory distress syndrome and many pneumonias. Hantaviral tibodies. Results of testing can be obtained within a few antigens are detected primarily in endothelial cells, and hours after the specimen is received in the laboratory.
those in the lung are heavily involved. Lesser amounts of Less commonly used serological tests, such as immuno- antigen are found in scattered endothelial cells through- fluorescent assay and particle agglutination, can also be out the body, as well as occasional involvement of mac- applied to hantaviral diagnosis (69).
rophages, myocytes, and many other cell types.
Initial detection of HPS-related hantaviruses was ac- In contrast to such diseases as South American hem- complished using heterologous hantaviral antigen (70).
orrhagic fevers, circulating antibodies appear early in the A more sensitive Sin Nombre recombinant nucleocapsid clinical course of HPS and often correspond to clinical antigen was developed in response to the outbreak in decline rather than improvement (73, 74). Thus, the im- 1993 in the United States; it is now widely used through- paired vascular permeability is thought to be immuno- out the Americas in ELISA tests for the detection of New logically mediated, probably strongly influenced by the World hantavirus infections. More recently, other recom- binant antigens have been developed, such as Andesvirus nucleocapsid. Due to the cross-reactive nature ofthese antigens, they cannot discriminate among closely TREATMENT
In fatal cases, fresh frozen tissue, fixed tissue, and blood There is no known effective antiviral therapy for HPS, can be used to confirm the diagnosis by RT-PCR, immu- although the drug ribavirin has shown a treatment effect nohistochemistry, or ELISA methods, respectively. Col- in reducing HFRS mortality (75). Open-label ribavirin treat- lection of blood clots from initial samples of all suspect ment had no obvious effect in a limited number of HPS cases is also recommended for subsequent RT-PCR on patients, and a placebo-controlled clinical trial is currently selected seropositive individuals. RT-PCR is a molecular under way in the United States. In the absence of a proven diagnostic technique targeting specific regions of the vi- pharmacological treatment and in light of the rapid pro- rus genome and is available only at selected research gression of HPS, effective clinical management depends laboratories. RT-PCR is not recommended for routine heavily on careful fluid management, hemodynamic moni- diagnosis, but is valuable in defining the virus genotype, toring, and ventilatory support. Therapeutic responses to searching for new viruses, and performing certain epi- shock in patients with HPS must be guided by an under- demiological studies. Immunohistochemistry is particu- standing of the underlying pathophysiology of this disor- larly well suited to retrospective diagnosis. Viral inclu- der, that is, profound pulmonary capillary leak in the pres- sions have rarely been observed in pulmonary capillary ence of primary myocardial pump dysfunction.
endothelial cells by electron microscopy.
Experimental therapies have been used to treat severely Some Old World hantaviruses have occasionally been ill patients with HPS. These include extracorporeal mem- isolated from patient serum or whole blood drawn within brane oxygenation (ECMO) and nitrous oxide inhalation.
three to nine days of onset of illness. However, propaga- Experience is very limited in the use of these experimen- tion of hantaviruses is difficult and this is not a recom- tal measures to treat HPS patients, and they have gener- ally been used only as a last resort form of therapy. Thereare no clinical data on the effectiveness of administeringimmune plasma to treat HPS patients. While this therapy PATHOGENESIS
has been effective for Argentine hemorrhagic fever (AHF),the differences in immune response and pathophysiol- The pathogenesis of HPS is related to a profound abnor- ogy between AHF and HPS suggest it is unlikely to be mality in vascular permeability. The capillary leak syn- drome is virtually confined to the lungs, and chest radio- Antiviral therapy with a drug such as ribavirin may be graph series typically chronicle the rapid onset of diffuse, more effective if given to patients identified very early in bilateral interstitial, and later alveolar, pulmonary edema the prodromal stage. Such patients might be close con- (64). There is also evidence for myocardial failure as an im- tacts of a confirmed HPS case (about 10% of hantavirus portant component of the shock syndrome observed (65).
cases occur in clusters, regardless of the issue of possible interhuman transmission of Andes virus) or persons with cause patients with this viral infection can deteriorate so very high risk exposure. Protocols should be developed to rapidly, a Swan-Ganz catheter should be inserted as soon permit controlled studies of early, expectant antiviral treat- as is clinically warranted. Intravenous crystalloid fluid is ment initiated prior to laboratory testing. Argentina has such used to maintain as low a wedge pressure (8–12 mmHg) a protocol that may be requested as a template.1 For every as is compatible with satisfactory cardiac indices (car- new procedure or therapeutic measure it is strongly rec- diac index >2.2 L/min/m2). Inotropic agents, such as ommended that controlled studies be performed.
dobutamine, dopamine, and norepinephrine, are begunearlier in the resuscitation of these patients than in theusual patient, rather than continued fluid boluses. The Initial Treatment of Hantavirus
use of loop diuretics such as furosemide is discouraged, Pulmonary Syndrome in the Emergency Room
since salt and water will be removed from circulating and During Transport
blood before being removed from the alveolar and inter-stitial compartments in the lung, thus exacerbating hy- Initial treatment during the observation period should potension. Red blood cells are usually not required to be directed to symptomatic and supportive measures, such maintain oxygen delivery unless hemoglobin concentra- as the control of fever and pain with paracetamol (avoid- tion falls below 8.5–10 g/dl. Thrombocytopenia has not ing the use of aspirin), antiemetics, and bed rest. The ob- required support with platelet transfusion. So far there is servation period could be managed at a primary care cen- no evidence that pharmacological doses of corticosteroid ter. However, if there is a high suspicion of HPS according offer any benefit in the treatment of HPS. Cardiac arrhyth- to the proposed HPS algorithm (Figure 2), patients should mias, particularly any episodes of electromechanical dis- be immediately transferred to an emergency room (ER).
sociation, portend a poor outcome and should be ag- Treatment in the ER should focus on maintenance of gressively treated. Renal failure and need for hemodialysis blood pressure and oxygenation while transfer to an in- is rare among Sin Nombre virus infections but was re- tensive care unit (ICU) is organized. When patients ported for two HPS cases due to Andes virus in southern present with shock to the ER, the case fatality rate ex- Argentina and Chile. Extracorporeal membrane oxygen- ceeds 80%. In contrast, the case fatality rate is 10% in ation (an experimental procedure) should be considered the absence of shock at this time, indicating the impor- when available if the serum lactate level exceeds tance of cardiogenic shock as a cause of death. While 4 mmol/l and cardiac index <2.2 L/min/m2.
some patients may have fluid requirements of 1 to 2 L Due to the extensive differential diagnosis, all pa- due to vomiting and diarrhea, it must be kept in mind tients should be treated for more common events, such that excessive fluid resuscitation will exacerbate the pul- as sepsis. A broad-spectrum antibiotic such as intrave- monary edema without commensurate improvement in nous ceftriaxone or ampicillin-sulbactam, as well as cardiac output. Early use of inotropic agents (see Sec- doxycycline used to treat rickettsioses, ehrlichioses, tion 7.8.2) may be necessary, depending on the ability plague, and tularemia, should be administered until to monitor response to therapy. Due to the rapid onset either HPS is confirmed or another diagnosis is made.
of pulmonary edema, hypoxemia may deteriorate rap-idly over several hours, and continuous monitoring ofoxygenation by pulse oximetry is preferred.
Case Management in a Rural Setting
In rural settings without access to intensive care facili- Treatment in the Intensive Care Unit
ties, treatment of cases should focus on maintenance ofblood pressure and oxygenation. In addition, broad- Close monitoring of oxygenation is extremely impor- spectrum antibiotics such as suggested in Section 7.8.2 tant so that timely intubation and mechanical ventila- should be administered until either HPS is confirmed or tion can be provided when required (when PAO /FIO another diagnosis is made. Intravenous crystalloid fluid falls below 150). Oxygen delivery is usually maintained should be used carefully so as not to exacerbate pulmo- until the cardiac index falls below 2.2 L/min/m2. Me- nary edema. It is recommended that fluid balance be main- chanical ventilation is required for about two-thirds of tained, with replacement fluid administered according to patients and typically lasts for five to seven days. Be- the amount lost. In case of shock, it would be necessary touse such inotropic agents as dobutamine or dopamine, even 1For further information contact Dr. Delia Enría, Instituto Nacional in the absence of cardiac monitoring. Oxygen delivery de Enfermedades Virales Humanas, Monteagudo 2510, 2700 should also be initiated early on, and a nonrebreathing mask Pergamino, Argentina; Telephone: (54-477) 29712/14; Fax: (54-477)33045; E-mail: [email protected].
could be used to ensure 100% oxygen concentration.

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