Hantavirus pulmonary and cardiovascular syndrome

Abstracts

Hantavirus pulmonary and cardiovascular syndrome is a recently identified and often fatal disease, which presents as acute respiratory distress syndrome (ARDS). Since the first outbreak, in Nov/Dec 1993, in Juquitiba, Brazil, 226 cases have been registered by FUNASA (National Health Foundation).(4) The disease occurs in previously healthy subjects, presenting with fever and symptoms similar to the common cold, and may rapidly evolve to pulmonary edema, respiratory failure and shock. Hemoconcentration and thrombocytopenia are common features, and the typical radiological finding is a bilateral diffuse interstitial infiltrate that evolves to alveolar consolidations in parallel to the worsening of the clinical condition. Initially, mortality was around 75%, but it declined to approximately 35% in the last few years. Patients who survive usually recover completely, about a week after the onset of the respiratory symptoms. The causal agent is a previously unrecognized hantavirus whose natural reservoirs are rodents of the family Muridae, sub-family Sigmodontinae. Specific antiviral treatment for hantavirus pulmonary and cardiovascular syndrome has not yet been well established, and the efficacy of ribavirin is currently being studied. Intensive care, including mechanical ventilation and invasive hemodynamic monitoring, is required for the more severe presentations of the disease. These measures may improve the prognosis and survival of patients with hantavirus pulmonary and cardiovascular syndrome if started early in the course of the disease.

Hantavirus pulmonary syndrome; Hantavirus infections; Brazil

A síndrome pulmonar e cardiovascular por hantavírus é uma doença de conhecimento relativamente recente e freqüentemente fatal, apresentando-se como síndrome do desconforto respiratório agudo. No Brasil, desde o primeiro surto, relatado em novembro/dezembro de 1993, em Juquitiba, 226 casos já foram registrados pela Fundação Nacional da Saúde. A doença afeta indivíduos previamente hígidos, apresentando-se com pródromo febril e sintomas semelhantes aos de um resfriado comum, podendo rapidamente evoluir para edema pulmonar, insuficiência respiratória aguda e choque. A hemoconcentração e a plaquetopenia são comuns da síndrome pulmonar e cardiovascular por hantavírus, e o quadro radiológico típico é de um infiltrado intersticial bilateral difuso, que progride rapidamente para consolidações alveolares, paralelamente à piora do quadro clínico. A mortalidade inicial era em torno de 75% e declinou para aproximadamente 35%, nos últimos anos. Os pacientes que sobrevivem geralmente recuperam-se completamente, cerca de uma semana após o estabelecimento do quadro respiratório. O agente causal, não reconhecido até há pouco, foi identificado como um hantavírus, cujo reservatório natural são animais roedores da família Muridae, subfamília Sigmodontinae. O tratamento específico antiviral ainda não é bem estabelecido, estando em estudo a eficácia de ribavirina. Cuidados de terapia intensiva como ventilação mecânica e monitoramento hemodinâmico invasivo são necessários nas formas mais graves da doença. Essas medidas, se instituídas precocemente, podem melhorar o prognóstico e a sobrevida dos pacientes com síndrome pulmonar e cardiovascular por hantavírus.

Síndrome pulmonar por hantavírus; Infecções por hantavirus; Brasil

REVIEW ARTICLE

Hantavirus cardiopulmonary syndrome^*

Mariangela Pimentel Pincelli^I (te sbpt); Carmen Sílvia Valente Barbas^II (te sbpt); Carlos Roberto Ribeiro de Carvalho^III (te sbpt); Luiza Terezinha Madia de Souza^IV; Luís Tadeu Moraes Figueiredo^V

^IDoctoral student of Pulmonology, Pulmonologist, Intensive Care Physician and Specialist as designated by the Brazilian Society of Pulmonology and Phthisiology

^IIAssociate Professor of Pulmonology, Physician in the Respiratory Intensive Care Unit and Specialist as designated by the Brazilian Society of Pulmonology and Phthisiology

^IIIAssociate Professor of Pulmonology, Head of the Respiratory Intensive Care Unit and Specialist as designated by the Brazilian Society of Pulmonology and Phthisiology

^IVDirector of the Virology Department at the Adolfo Lutz Institute

^VAssociate Professor and Director of the Multidepartmental Unit for Virology Research

^{Correspondence}

ABSTRACT

Often referred to as hantavirus pulmonary syndrome, hantavirus cardiopulmonary syndrome (HCPS) is a recently identified and often fatal condition that presents as acute respiratory distress syndrome. The first outbreak in Brazil occurred in 1993 in the city of Juquitiba. Since then, 226 cases have been registered by the National Health Foundation. The disease occurs in previously healthy subjects and initially presents as fever, accompanied by symptoms similar to those of the common cold. However, it may rapidly evolve into pulmonary edema, respiratory failure and shock. Hemoconcentration and thrombocytopenia are common features, and the typical radiological finding is bilateral diffuse interstitial infiltrate that evolves to alveolar consolidation that parallels the worsening condition. Initially, mortality was approximately 75% but has declined over the last few years to roughly 35%. Patients who survive usually recover completely within a week or so after the onset of the respiratory symptoms. The causative agent is a previously unrecognized hantavirus whose natural reservoir is a wild rodent (Muridae: Sigmodontinae). Specific antiviral treatment for HCPS has not yet been well established, and the efficacy of ribavirin is currently being studied. Intensive care, including mechanical ventilation and invasive hemodynamic monitoring, is required for the more severe presentations of the disease. If started early in the course of the disease, these measures may improve prognosis and survival in HCPS patients.

Key words: Hantavirus pulmonary syndrome/diagnoses. Hantavirus infections/diagnoses. Brazil.

Abbreviations used in this paper:

HFRS – hemorrhagic fever with renal syndrome

FUNASA – Fundação Nacional de Saúde (National Health Foundation)

RT-PCR – Reverse transcriptase-polymerase chain reaction

ARDS – Acute respiratory distress syndrome

HPS – Hantavirus pulmonary syndrome

HCPS – Hantavirus cardiopulmonary syndrome

TNF – Tumor necrosis factor

Introduction

Hantavirus pulmonary syndrome (HPS) was first recognized in 1993 in the semi-arid southwestern region of the USA, in the states of Arizona, New Mexico, Colorado and Utah.^(1-3) During this initial outbreak, mortality reached approximately 80%.⁽²⁾ After numerous diagnostic tests, it was observed that patient serum reacted against known hantaviruses which had caused hemorrhagic fever with renal syndrome (HFRS) in Eurasia.^(1-3) The weak serologic reactivity suggested that the North-American outbreak involved a type of hantavirus as yet unrecognized. About 8 weeks after the first cases were reported, it was determined that HPS was caused by a new hantavirus,⁽⁴⁾ one that was fundamentally different from HFRS.^(2,3,5–70). More recently, it was recognized that cardiovascular collapse plays an important role in the high mortality of this syndrome, and it has come to be known in some circles as hantavirus cardiopulmonary syndrome (HCPS).^(3,8)

The causative agent, analyzed from genetic amplification of viral particles obtained from autopsies was initially called Four Corners, Muerto Canyon or Little Water, alluding to the sites where the cases originated.^(4–7) However, after complaints from local residents worried about their town names being associated with such a lethal virus, the virus came to be known as the Sin Nombre ("no name") virus, as a pun.^(7,9,10)

Also in 1993, the reservoir for the Sin Nombre virus was identified: a rodent known as the deer mouse (Peromyscus maniculatus), captured in the vicinity of the houses of infected people.^(4,11,12) In the rodent, the virus causes a chronic infection, apparently without provoking disease. The viral particles are emitted through the saliva, feces and, especially, the urine of the animal.

Hantavirus and its reservoirs

Hantaviruses are RNA viruses, round, enveloped and measuring approximately 80 to 120 nm. The viral RNA is a simple ribbon, with 3 segments and a negative polarity. The RNA segments are designated: L (large), which codify viral transcriptase, M (medium), which codify the glycoproteins of the capsule or S (small), which codify the protein of the viral nucleocapsid.^(2–4,7)

The name Hantavirus refers to Hantaan, the first virus of the kind, described in 1976 after being isolated from a rodent in Korea, at a site close to the river of that name.⁽¹³⁾ At that time, approximately 3,700 cases of HFRS were reported.⁽¹⁴⁾ However, the disease was previously known as Korean hemorrhagic fever and affected the American troops who fought there during the 1950s.⁽¹⁵⁾

Currently, HFRS has an incidence of 100,000-200,000 cases annually, most occurring in China. In Asia, hantaviruses are mainly associated with rodents of the family Muridae and, in Europe, with the subfamily Arvicolinae.^(14–16)

Among the Eurasian hantaviruses, the primary host for the Hantaan virus is the field mouse Apodemus agrarius. The Dobrava virus, which also causes severe HFRS in Asia and Eastern Europe is associated with the rodent Apodemus flavicollis. The Seoul virus conveys a less severe form of the disease, with a less than 1% mortality rate, which has been identified mainly in Asia and whose primary host is the Rattus norvegicus. Also, the Puumala virus is responsible for a mild form of HFRS, especially in Scandinavia and Eastern Europe, and its primary host is the rodent Clethrionomys glareolus.^(14–16)

In the Americas, after 10 years of study, several hantaviruses have been recognized. In North America, the Sin Nombre virus seems to be the causative agent in most cases of HCPS,^(14-18) whereas in South America, the Andes virus has been implicated in most of the cases arising in Chile and Argentina.^(20–23) Phylogenetic differences among the hantavirus species are directly related to the geographical distance between the sites where the virus has been detected.^{(19–21,24,25)}

The hantaviruses which cause HCPS are associated with American wild rodents of the Muridae family, subfamily, Sigmodontinae. This subfamily comprises about 430 species, including wild rodents that are different from those known to urban dwellers. These rodents, such as the domestic rat, the black rat and the Norwegian rat (the latter from the subfamily Murinae), have their origins in the so-called "Old World". However, some wild species of the subfamily Sigmodontinae may infest rural homes and suburban areas. ^(26-28) A third group of rodents, of the subfamily Arvicolinae, are reservoirs for other hantaviruses which do not cause HCPS. ^{(12,18, 29,30)}

The main host for the virus Sin Nombre is the deer rat (Peromyscus maniculatus), a rodent present in the rural areas of most of North America, especially areas west of the Mississippi river.^{(12,18,19,30)} In addition to the virus Sin Nombre, other hantaviruses which cause HCPS in North America are the New York virus, which is associated with the white-footed mouse (Peromyscus leucopus), the Black Creek Canal virus, whose reservoir is the cotton rat (Sigmodon hispidus) and the Bayou virus, carried by the rice rat (Oryzomys palustris). The Prospect Hill virus, also found in the USA, is not associated with any human diseases.^{(14,15,17,18)}

Several species of hantavirus have been associated with HCPS in South America: Juquitiba, Castelo dos Sonhos and Araraquara (all in Brazil)⁽²⁵⁾; Laguna Negra (in Bolivia and Paraguay); Oran , Lechiguanas and Mermejos (in North and Central Argentina); and the Andes virus (in Chile and Argentina).^{(21-23,26,27)} In Brazil, antibodies against hantavirus have been detected in the field mouse (Hesperomyinae Akodon), pygmy rice rat (Oligoryzomys microtis) and bushy-tailed rat (Bolomys lasiurus sp. ^(28,31)

Hantavirus evolution seems to parallel that of the reservoir rodent, and there is evidence that this surprising co-evolution has been happening for thousands of years.^(24,27,28) Viral genetic fragments have been found incorporated into the mitochondrial RNA of the rodents. ⁽²⁴⁾

Hantaviruses belong to the Bunyaviridae virus family. In contrast to the other members of this family, there is no evidence that hantaviruses are transmitted by arthropods.^(14,15)

Transmission

The presence of hantaviruses in infected rodent saliva, as well as the hypersensitivity of these rodents to viral inoculation through intramuscular injection, support the hypothesis of horizontal (rodent-to-rodent) transmission. This is likely linked to competition for food among individuals of the same species when food shortages follow periods of greater fertility.^{(3,11,29,32,33)} During the outbreak in the Four Corners region, 30% of the captured rats were found to be infected.^(29,30) Most of the infected rats were adult males, a fact which may be attributable to their more competitive and aggressive behavior.^(11,27-29)

Transmission of hantavirus to human beings occurs through inhalation of aerosolized viral particles present in rodent excreta and saliva.^{(11,12,18,29)} Although infrequent, transmission may also occur as a result of a bite from a contaminated animal, inoculation through broken skin or mucosa, or even consumption of food or water contaminated by the virus^{(11, 29)} (Figure 1).

Although hantavirus causes a life-long infection in rodents, there is a period of greater emission of viral particles 3 to 8 weeks after initial infection. Predatory animals, such as dogs, cats and coyotes, can also become infected, but are less likely to transmit hantavirus to other animals or to human beings. However, domestic animals may bring infected rodents into contact with human beings.^{(2,3,29,30,33,34)}

In 1996, an outbreak of Andes virus was reported in the vicinity of Bariloche, Argentina. After epidemiological and phylogenetic studies, interpersonal viral transmission was confirmed, including transmission to five physicians and other health care professionals. Two persons who had not visited the site where the outbreak occurred, were contaminated in Buenos Aires, after the patients had been transferred from the initial site to the hospital. This raised the suspicion, later confirmed, of interpersonal transmission of HCPS.^(35,36)

Epidemiology

Despite the fact that the syndrome was initially described in the USA, according to data published in 2001 by the Organização Pan-Americana da Saúde (Pan-American Health Organization), South America has surpassed North America in terms of number of HCPS cases, especially due to occurrences in Argentina, Brazil and Chile⁽³⁴⁾ (Figure 2). There is evidence that infections from the Andes virus in suburban areas in Argentina and Chile may have been present but unidentified for some time.⁽²⁸⁾

In the same year that HCPS was described, 1993, the first outbreak was reported in Brazil. It occurred in the Juquitiba area, in a recently deforested part of the Serra do Mar mountain range. Three brothers all acquired the disease over the span of a few days. This initial outbreak resulted in the death of 2 of the brothers and the identification of the Juquitiba virus.⁽³⁷⁾ Later, also within the state of São Paulo, new cases were reported in Araraquara and Franca, and cases were also reported in Castelo dos Sonhos (in the state of Mato Grosso), resulting in the subsequent identification of yet further new hantavirus strains.^{(25,32-34,38)}

Data provided by the Fundação Nacional de Saúde (FUNASA – National Health Foundation) allow us to delineate the epidemiological profile of the disease in Brazil. In the initial years, the cases reported came predominantly from the state of São Paulo. In 2000 and 2001, a great number of cases was observed in Paraná ⁽³⁹⁾ and Santa Catarina. In 2002, the cases were more evenly distributed among the Southern and Southeastern states⁽³⁸⁾ (Figure 3).

Due to a significant outbreak there in 2000, the state with the greatest number of reported cases is Paraná. The state of São Paulo is second, followed by Minas Gerais, Rio Grande do Sul and Santa Catarina^(38,39) (Figure 4). From October 1993 to October 2002, 226 HCPS cases were reported in Brazil. An increasing number of reports of HCPS and a lower mortality have been noticed in recent years (Figure 5). Mean mortality in Brazil is now approximately 34%. There is no predominance regarding gender and the age group most affected is that of young adults, perhaps reflecting a tendency for exposure to rodents during working activities. ^{(38, 39)}

Several factors should be taken into consideration in the epidemiological study of this emerging zoonosis in order to understand its appearance. Geographical and historical studies of the region are important, as well as data regarding special occupations, work and production structures, migration patterns, ethnic distribution, rodent behavior dynamics and their relation with the different viruses, as well as changes in the ecosystem and environmental determinants.^{(20,28,31-33,40)} Studies involving the capture of wild rodents in the state of São Paulo showed that serum antibodies against hantavirus are present in Akodon sp (forest mice), Oligoryzomys sp (pygmy rice rats) and mainly, Bolomys lasiurus (bushy-tailed rats), suggesting that they are the reservoirs for these HCPS-causing agents.^(25,28,31)

The increased numbers of cases are likely associated with an increase in the wild rodent population or behavioral changes within that population as a result of habit imbalances brought about by human activity. In the state of São Paulo, the majority of HCPS cases occur between April and July. This corresponds to the beginning of the dry season, the beginning of the sugar cane harvest, which involves burning off the sugar cane fields, and to the appearance of certain kinds of grass seeds enjoyed by wild rodents.^{(28,31-34,41,42)} In the state of Paraná, it has been determined that agricultural activities related to pine trees constitute an important risk factor for the development of HCPS , which usually occurs in the second semester.⁽³⁹⁾

In the USA, some situations were observed to be epidemiologically related to HCPS and are summarized in ^{Diagram 1}.^{(3,11,26,29,30,43)}

Under environmental conditions (outside the host), the viruses probably survive for a period shorter than a week indoors and even less when exposed to sunlight in external areas. ^(42,43)

Brazilian hantaviruses associated with HCPS were detected mainly through amplification of part of their genome through reverse transcriptase-polymerase chain reaction (RT-PCR). The nucleotides of the viral genomic fragments were sequenced and compared through phylogenetic analysis to those of other known hantaviruses. Analyzed through this methodology, the Araraquara and Castelo dos Sonhos viruses showed genomic homology of 78.5% when compared to the Andes and Laguna Negra viruses, thereby confirmed them as hantaviruses.⁽²⁵⁾ In addition, comparison between the Araraquara and Castelo dos Sonhos viruses showed a genomic homology of 78.9 to 82.8%, suggesting they are two distinct viruses that circulate in regions of the country distant from one another, possibly with different reservoir rodents. ⁽²⁵⁾

Nucleotides obtained from the blood of patients with HCPS in the region of the city of Ribeirão Preto in the state of São Paulo were sequenced through RT-PCR involving amplicon reference fragments and showed high homology with Araraquara hantavirus (87.7% to 96.5%). This suggests that the Araraquara virus is responsible for the disease in that region.⁽⁴⁴⁾

Curiously, serum-epidemiological studies which analyzed hantavirus infection levels in the population from Ribeirão Preto did not support the epidemiological data observed in patients with HCPS, who had clear connections or contact with rural environment. In 1999, a serological survey showed IgG antibodies against recombinant antigens of the protein N of the Sin Nombre virus with the ELISA method – 567 samples were tested and 1.23% of them resulted positive.⁽⁴⁵⁾ Such results suggest that hantavirus infection is not rare in the region of Ribeirão Preto and that its frequency is two times higher than that observed in the USA among populations at high risk of being infected by such microorganisms.^(3,43)

It was also possible to interview 6 of the 7 patients who presented antibodies against hantavirus in this serological survey, and all of them denied having had previous severe pulmonary diseases. This observation suggests that infection by hantavirus may be subclinical or present as a milder form than those originally described for that region.^{(28,32,33,41,44–46)}

In 2001, as a follow up to the above study, a serological survey was performed at random in the city of Jardinópolis. A total of 818 individuals took part in the study and their ages varied from 15 to 70. Andes hantavirus IgG antibodies were detected by ELISA in 14.3%.^(32,46) No predominance of positive results in the serum in related to gender, age, contact with rodents or previous severe pneumonia was observed. These results support the hypothesis that infections by hantavirus are frequent in the studied region and possibly in other regions of the country as well. These results could also indicate coexistence with another type of hantavirus, causing less severe or sub-clinical infection, which would not be suspected or diagnosed. The rare and most severe manifestation of the disease, HCPS, could be determined by some factor, possibly genetic, which could be present in a minority of individuals among the great number of infected persons.^{(32,42,44-46)}

Clinical Presentation

Despite the fact that more than 200 cases of HCPS have been reported, only a few clinical series studies have been conducted.^{(32,33,37,47,48)} In order to better analyze the clinical presentation of HCPS among us, we have used the sum of these series as our demographic. Special attention was given to the series of 14 patients from Ribeirão Preto^(32,33) and to a series of 8 cases from Uberaba.⁽⁴⁷⁾ In addition, the 3 initial patients from Juquitiba⁽³⁷⁾ and 1 case from Anajatuba⁽⁴⁸⁾ were considered so that we could establish similarities and peculiarities of the presentation of HCPS in Brazil.

Incubation Period

The study of patients with well-defined and isolated exposure to rodents allowed us to establish the incubation period for HCPS at between 9 and 33 days (median, 14 to 17 days). In addition, activities and behavior that increase risk for acquisition of the disease have been determined.⁽⁴⁹⁾

Prodromal Phase

In most of the cases reported in Brazil, HCPS developed in a similar way. The signs and symptoms in the beginning of the disease included fever, asthenia and headache. In the prodromal phase, the patients presented no coughing, rhinorrhea or other respiratory symptoms. Also in this phase, shivering, nausea and vomiting occurred, and abdominal pain and diarrhea were not uncommon.

In the USA, in a series of 44 patients reported by Zaki et al.,⁽⁵⁰⁾ the mean length of the feverish prodrome was 3 days, and preceded the search for medical help. The most frequently reported symptoms were also fever and myalgia. Gastrointestinal disorders, such as nausea, vomiting, abdominal pain, occurred in approximately 50% of cases. In the epidemics of HCPS caused by the Andes virus in Argentina, prodromes with fever, myalgia and malaise were also observed. In those patients, gastrointestinal symptoms were less common (5%).^(20,22,23)

Contrary to what was observed for the Sin Nombre virus,⁽⁵¹⁾ myalgia was present in only 38% of the Brazilian cases.^(32,33)

In the prodromal phase, viremia occurs and the levels of antigens are as elevated as in AIDS or hepatitis C. Nevertheless, identification of hantavirus in biological material obtained from human beings is difficult.^(52,53)

Cardiopulmonary phase

Generally, after the third day of infection, a dry cough appears and later becomes productive, with bloody sputum. Dyspnea also develops and is, initially, mild in intensity but, in the majority of cases, develops in less than 24 hours into severe respiratory failure requiring ventilatory support.^{(3,32-34,42,51)} (Table 1).

In the cases reported in Brazil, dyspnea at rest or at minimal exertion was followed by cough with expectoration of bloody secretion, pulmonary rales, tachycardia and arterial hypotension, followed by circulatory collapse. In this phase of the disease, in addition to hypoxemia, the hematocrit is increased and leucocytosis with a shift to the left is observed, together with abnormal lymphocytes in peripheral blood smears and low platelet counts. Levels of serum creatinine are also elevated due to decreased renal blood flow.^(32-34,47)

The appearance of acute pulmonary edema and myocardial depression in patients with HCPS are related to an intense immunological reaction in which neutralizing antibodies are produced and cell response is activated. In addition, cytokines, platelet activating factor (PAF) and tumor necrosis factor (TNF) are released. ^(52-54)

The laboratory test abnormalities include mainly: increase in hematocrit, leucocytosis with a shift to the left, abnormal lymphocytes in blood smears and fewer platelets. Moderate increases in liver enzymes – alanine transaminase and lactic dehydrogenase – may also occur.^{(18,32-34,51)}

The kinds of hantavirus infection seen in South America involve clinical presentations that vary from asymptomatic infections and mild disease to HCPS. Renal impairment was observed in several cases. Between 30% and 70% of the Andes virus cases presented hemorrhagic disorders of varying degrees of severity, and 6% developed renal failure, requiring transient dialysis.^(20-22)

As for the more severe forms of cardiopulmonary injury, Crowley et al., in 1998, made a retrospective analysis of the cases treated at the University of New Mexico Hospital in the city of Albuquerque New Mexico (reference center for patients from the Four Corners region). The authors determined that the presence of any of the following: cardiac index < 2.5 L/min/m², serum lactate > 4.0 mmol/L, electrocardial activity without pulse or ventricular fibrillation, or shock refractory to volume and vasoactive amines administration was related to a 100% mortality risk.⁽⁵⁵⁾

Recovery phase

The recovery of patients with HCPS, especially those who required orotracheal intubation with mechanical ventilation usually requires a prolonged amount of time, taking several weeks, mainly due to the nutritional consequences of a severe disease, as well as to nosocomial pneumonia.^(3,18,33,34)

Of late, medical evaluation of HCPS cases has shown sequelae such as chronic fatigue and lung function restriction, with adverse consequences on quality of life in more than 30% of the North American HCPS patients. ⁽⁵⁶⁾

In Brazil, 2 patients who survived HCPS, one of each genders and aged 16 and 31, were re-evaluated 30 months after the acute phase. They had no symptoms or complaints after hospital discharge. Upon clinical examination, no pathological changes were found. Chest tomography was normal for both patients and lung function tests also showed results within the normal range.⁽³²⁾

Differential diagnosis

In the differential diagnosis of HCPS, one should consider viral pneumonitis (such as that caused by the influenza virus or measles), atypical pneumonia caused by mycoplasma and Legionnaires’ disease, leptospirosis, Q fever, tularemia, septicemic plague, histoplasmosis, hemorrhagic dengue or, in patients with impaired immune function, pneumonia from Pneumocystis carinii and cytomegalovirus infections, Cryptococcus and Aspergillus ^{(5,8,18,33,34,51)}

The absence of nasal symptoms, such as nasal discharge, sneezing and obstruction during the prodromal phase, makes it easy to differentiate HCPS from the common cold.

In our environment, pneumonia by Pneumocystis carinii as first manifestation of AIDS and hemorrhagic dengue in cases with pleural effusions is an important differential diagnosis with HCPS.^(32-34)

Atypical presentations

Recently, Passaro et al. described a case of pyelonephritis that progressed to respiratory failure and death. A diagnosis of Sin Nombre virus-related HCPS had been confirmed through serology and genetic viral sequencing performed at the Centers for Disease Control and Prevention (CDC) in the USA.⁽⁵⁷⁾

In 1999, Zavasky et al. published a report of 2 cases of infection by the Sin Nombre virus without respiratory changes, calling attention to a broader spectrum of the disease.⁽⁵⁸⁾

From what may be inferred from serological surveys in the general population and from other countries in South America,^(21,27) there probably are milder or subclinical forms of the disease in Brazil that are undiagnosed or misdiagnosed.^{(32,42,45,46)}

Radiological diagnosis

The characterization and recognition of radiological changes caused by HCPS is important in the identification of the syndrome and in the determination of a prognosis.⁽⁵⁹⁾

In 1994, Ketai et al. published a study of a series of 16 patients with clinically and laboratory test-proven HCPS,⁽⁶⁰⁾ according to CDC definition. ⁽⁶¹⁾ In 13 (88%) of those patients, radiological changes such as Kerley B lines, peribronchiolar thickening and ill defined outline of the pulmonary hilum were observed in the initial chest X-ray, indicating interstitial edema (Figure 6). Such changes are less evident in ARDS and aid in the differential diagnosis.^{(62, 63)}

An additional 3 patients presented normal chest radiographs initially, although all developed signs of interstitial edema within the subsequent 48 hours. ⁽⁶⁰⁾

Four patients manifested mainly interstitial disease over the entire course of the disease and all survived,⁽⁶⁰⁾ indicating that the absence of progression to alveolar flooding may be an indicator of better prognosis in HCPS.

Initial chest X-rays revealed alveolar flooding in 6 patients. After the first 48 hours, 11 patients presented bilateral extensive alveolar infiltrates (defined as encompassing more than half of both pulmonary fields). All of those patients were in respiratory distress: 8 required mechanical ventilation and 6 died, ⁽⁶⁰⁾ indicating a worse prognosis in the extensive forms of alveolar pattern (Figure 7).

In addition, every patient had a cardiothoracic index < 55% without indication of increase in cardiac chamber size. The vascular pedicle was normal in 14 patients^{(60, 62)} (normal being a thickness of up to 5.3 cm in standing x-ray and up to 6.3 cm in supine x-rays ⁽⁶⁴⁾)

Pleural effusion is also common. In the reported series, it was found in 11 patients. It was already visible in the initial x-ray of 2 patients and developed in the first 48 hours in 9 patients. ⁽⁶⁰⁾

As distinctive characteristics of ARDS,⁽⁶⁰⁾ the absence of peripheral distribution of the alveolar infiltrate and the presence of interstitial edema at the onset of HCPS stand out. A previous study⁽⁶³⁾ of radiological alterations in ARDS showed peribronchiolar thickening and Kerley B lines in less than 10% of the sample. Also, the early appearance of pleural effusion is rare in ARDS.^(62–64)

The subsequent alveolar flooding appears in most patients with pulmonary hantavirus and tends to have a basilar and perihilar distribution instead of the peripheral as observed in ARDS.^{(62, 63)}

In a recent study, performed in Canada by Boroja et al., no mortality was observed in patients with non-extensive forms of radiological alterations when there was predominance of interstitial or alveolar-interstitial patterns.⁽⁵⁹⁾

Etiological diagnosis

In Brazil, the laboratory-based diagnosis of hantavirus infection in humans is usually made with the ELISA serological method, which aims to detect mainly M antibodies associated with recent infection. Such diagnosis is possible, even in the acute phase of the disease, because the antibodies in HCPS appear together with the development of signs and symptoms.^{(2,3,23,27,33,34,43)}

Serological methods for the detection of specific IgG antibodies have been more extensively used in epidemiological surveys. In these tests, antigens from the Sin Nombre virus⁽⁶⁵⁾ or Andes virus⁽⁶⁶⁾are used. These antigens are produced by direct purification of viral material after inactivation or, preferably, they are recombinant proteins produced in bacteria, such as the proteins N or G1 from the viral surface. Both are important viral antigens.

Other serological methods less used in the diagnosis of infections by hantavirus are indirect immunofluorescence with hantavirus infected cells in spot-slides and Western blot. ⁽⁶⁷⁾

The RT-PCR method, which detects the hantavirus genome in clinical material proved extremely useful and practical for the diagnosis of HCPS. It is a quick and simple technique which can be performed in laboratories without special safety conditions that would be recommended for hantavirus isolation in cell cultures. ^{(3, 43)} To perform the RT-PCR, the RNA is extracted from the blood or serum. Material from rodents can also be processed in this way. After the extraction of the RNA, a specific primer for a region of the virus genome is used and, with the help of the reverse transcriptase (RT) enzyme, the fragment of viral genome is transformed into complementary DNA which, in turn, oriented by a pair of primers, is amplified a million times by polymerase chain reaction (PCR) in thermal cycles that use a heat-resistant enzyme, TaqDNA polymerase. The presence of amplified genomic viral segments may thus be detected through a simple chemical reaction.

To perform RT-PCR, the sample must be shipped to the laboratory no less than 12 hours after sampling. The samples should be kept at 4ºC during transport. Samples may be stored for long periods in liquid nitrogen or in freezers at –70ºC.⁽⁶¹⁾

The nucleotides of the product amplified by PCR may be sequenced and, by comparison with the known hantavirus genomes, the causative agent and its phylogenetic relationship with other microorganisms of the same gender may be determined, even permitting inferences to be made regarding the reservoir rodent. ^{(3, 25, 27, 28)}

The phylogenetic analysis of hantavirus in the Americas shows that the Brazilian viruses Juquitiba, Castelo dos Sonhos and Araraquara are very similar to other South-American hantaviruses, particularly Andes and Laguna Negra.⁽²⁵⁾

Hantavirus isolation should be carried out in the laboratory with level 3 safety equipment, which protects against potential accidents in which the virus might escape the premises or contaminate laboratory workers.^(43,44) Isolation of the virus in biological material obtained from HCPS patients or from rodents is usually performed through inoculation of such materials into cultures of cells from the kidneys of the African green monkey (VERO E6). The virus, thus isolated, may by identified through immunofluorescence or RT-PCR.^{(43,44,67,68)}

Laboratory-based diagnosis

Since the definitive diagnostic methods for detection of HCPS (serological and viral detection) are not available to ordinary laboratories, the most frequent laboratory-based changes found in HCPS should serve as indicator of high probability of infection.^{(3,18,27,32-34)}

In 2001, Koster et al. published a study of 52 patients with HCPS confirmed by specific serological tests. They analyzed peripheral blood smears from those patients and compared them to 128 smears that were negative for HCPS upon serology. They showed that, during the prodromal phase, low platelet count is the only abnormality consistently observed, and should be interpreted as an indication for performing specific serological tests.⁽⁶⁹⁾ In addition, they determined that finding 4 of the 5 characteristics presented in ^{Diagram 2} provided a diagnosis of HCPS with 96% sensibility and 99% specificity, without false negatives among the patients who developed more severe forms and required intensive care. They also determined that low platelet count was the only finding consistently observed during the prodromal phase of the disease.⁽⁶⁹⁾

Based on those findings and on epidemiological data from the changes most frequently found in our patients, Figueiredo et al. (5, 9, 43) and Campos et al. (32,46) designed a flow chart for the diagnosis of HCPS (Figure 8).

The decision to send a patient to the ICU has been shown to be important in determining patient survival. Thus, it is recommended to try to determine which cases have worse prognoses and make the ICU facilities available to them.

As previously mentioned, the radiological finding of extensive alveolar pattern determines a negative prognosis,^{(59, 60)} as well as the cases with hemodynamic failure.⁽⁵⁵⁾

Maybe an early indicator of severity might be the determination of viral load: In 1999, Terajima et al. developed a quantitative essay using the technique of polymerase chain reaction (PCR), directed to viral reverse transcriptase. The authors showed the presence of a great number of viral particles in the blood of patients who developed HCPS, especially in the more severe and fatal cases. In those who survived, the number of viral particles decreased in parallel with the resolution of the fever.⁽⁵³⁾

Anatomical and pathological diagnosis

Material such as lungs and other organs harvested during the autopsies of fatal HCPS cases can be processed by immunohistochemical and hybridization methods in order to detect the presence of hantavirus through microscopy. The viral genome can also be detected in tissues through RT-PCR.^(50,70)

Studies performed soon after the initial outbreak in the USA determined the main pathological characteristics of the syndrome.^(51,70) In those studies, tissue samples from HCPS patients were examined through immunohistochemical technique with specific monoclonal antibodies (especially GB04-BF07, which reacts with all the known hantavirus serotypes) and polyclonal antibodies from the serum of recovering patients.

Zeki et al. observed 44 fatal HCPS cases. They determined the involvement of multiple organs with varying degrees of vascular congestion. The main histopathological characteristic, however, was the pulmonary involvement of mild to moderate pneumonitis found in 40 of the 44 cases. They observed varying degrees of edema, vascular congestion and mononuclear infiltrates. Characteristically, there were no vascular or necrotic thrombi or morphological changes in the endothelial cells. The respiratory epithelium was intact, without changes in the type I pneumocytes or evidence of cell debris, nuclear fragmentation or type II pneumocyte hyperplasia. ⁽⁵⁰⁾

Endothelial cells were also intact, but viral particles were frequently observed in their interior. The alveolar wall appeared to thicken in the presence of a great amount of extravasated protein material and erythrocytes. Inside the alveoli a great amount of fluid and rare hyaline membranes could be observed, but the intraalveolar infiltrate and cell debris, which are typical of ARDS, were absent in HCPS.^(50,70)

The mononuclear cell infiltrate was composed of cells with increased volume, which had the appearance of monoblasts. Cell-type characterization was performed in 5 patients and showed to be a mixture of activated T lymphocytes (CD3+) and cells of monocytic/monphagic lineage (KP1 and Ki-M1P+), with few neutrophils.⁽⁵⁰⁾

The presence of immunoblastic infiltrate, typical of HCPS, is important in the differential diagnosis with AIP (acute interstitial pneumonia). In AIP, histological evidence of organization can also be observed and is usually more prolonged and protracted.⁽⁷¹⁾

The presence of immunoblasts is also frequent in the spleen, especially in the red pulp and peri-arteriolar space, and in lymph nodes in the paracortical and sinusoidal regions. ^{(50, 70)} The bone marrow presents a moderate increase in cellularity, with an important shift to the left in myelopoiesis.⁽⁵⁰⁾

Physiopathology

In the anatomopathological studies, it was possible to determine that there is a viral tropism for endothelial cells, and viral particles were observed through histochemical methods and electronic microscopy in cells from capillary endothelium in several tissues. Electronic microscopy also showed a poor cytopathic effect in these cells.

The main change observed in HCPS was an increase in vascular permeability, which could explain the pulmonary edema, hemoconcentration and circulatory collapse seen in the syndrome.^(51,70,71)

It has been postulated that the alveolar epithelium in the lungs remains intact and retards the flooding of alveolar spaces, keeping a great part of the extracellular fluid inside the lung interstitium, thereby explaining the prominent interstitial edema with Kerley B lines and peribronchiolar thickening which are observed in initial chest X-rays (Figure 6).

On the other hand, in HFRS, there is a predominance of vascular changes in the retroperitoneal compartment, including the kidneys.⁽⁷¹⁾

Both HCPS and HFRS are human diseases caused by hantavirus and result from impairment of endothelial and platelet functions. The pathogenesis of such impairment seems to be mediated by interaction of viral glycoproteins and beta-3 integrins, which are present in endothelial cells and in platelets.^{(32-34,72,73)} Since beta-3-integrins are critical receptors for platelet and endothelial cells adherence and regulate vascular permeability and platelet adhesion and activation, it is probable that the use of these receptors by hantavirus is fundamental to its pathogenic effects. ^{(72, 73)}

Humoral immune response seems to be important in the determination of survival. There is an early response with the synthesis of IgM, IgA and IgG. The detection peak for IgM coincides with one to two days after the beginning of symptoms and IgG peak occurs in the first week of the disease, whereas IgA has its maximal response around the 15^th day. Absence of low levels of IgG has been associated with higher mortality rates.

Immunohistochemical staining techniques have been performed for the study of material from autopsies of patients who died from HCPS. Mori et al., in 1999, described the finding of a large number of cells that produced cytokines (monokines: IL-1-alpha, IL-1-beta, IL-6 and TNF-alpha; lymphokines: gamma-interferon, IL-2, IL-4 and TNF-beta) in lungs and spleens of patients who died due to HCPS, suggesting that the local production of cytokines is important in the pathogenesis of the syndrome. In contrast, the authors observed few to no cytokine producing cells in lungs from patients who died due to ARDS and other diseases.⁽⁵⁴⁾

Support measures

It is important to point out that clinical suspicion and the knowledge of the early manifestations of the syndrome are essential in order to send the patient to the ICU, since aggressive cardiorespiratory support measures increase the probability of survival. ^{(3,18,27,3234)}

Ventilatory and hemodynamic assistance are of utmost importance in the more severe cases. Generally, tracheal intubation and positive pressure mechanical ventilation are necessary.

Hemodynamic adjustments are also very important and, in cases of circulatory shock concomitant with respiratory failure, monitoring with a catheter in the pulmonary artery (Swan Ganz) is indicated in order to achieve a better assessment of the hemodynamic profile of the syndrome: low cardiac index, low systolic volume, normal or low wedge pressure in the pulmonary artery and high peripheral vascular resistance. ^(8,55) Hemodynamic monitoring is also useful for a careful volume replacement and adequate pressure support.^{(3,8,18,27,32-34,55)}

Analysis of the volumes infused through parenteral administration in 10 HCPS patients showed a significant association (p=0.0152) between volumes greater than 2500 ml used in the first 24 hours of hospital treatment and death.⁽³²⁾ In such patients, the infused fluid tended to collect in the lungs, worsening the respiratory failure.^(5,24,25,34) Thus, in HCPS, it is important that hemodynamic stabilization be performed through a careful administration of vasoactive drugs, dobutamine being preferred, possibly combined with noradrenaline due to its effects on peripheral vascular resistance.

As for the ventilatory approach, lung protective strategies should be given preference, avoiding the use of high inspiratory oxygen fractions and limiting the pressure in the airways to avoid volutrauma, barotrauma and biotrauma.^(74,75)

Specific treatment

A clinical study was performed in China from 1985 to 1987, in which intravenous ribavirin was used in 242 patients with hantavirus-related HFRS. The resulting 4-fold decrease in mortality in the treated group (2% in 125 treated patients vs. 8% in 117 patients who received placebo) has led to ribavirin being widely used for treatment of HCPS, although its efficacy has not yet been fully established.⁽⁷⁶⁾ Although ribavirin is effective in vitro against hantavirus, its efficacy has not yet been proved in vivo. It seems probable that the drug would not have time to act when administered during the cardiopulmonary phase, in which immune mechanisms predominate.^(76,77)

Currently, there is an ongoing randomized, double blind, placebo-controlled, phase III study comparing the drug efficacy to that of placebo in the treatment of HCPS. In that study, ribavirin is used in patients > 12 years old, in 15 doses of 16 mg/kg/6 hours, after an initial bolus of 30 mg/kg, and then nine doses of 8 mg/kg/8 hours. The study is coordinated by the CDC and, at the moment, is still recruiting patients. The main adverse effect is transient anemia, which reverts upon withdrawal of the medication.⁽⁷⁶⁾

Prevention

The strategies for prevention are very important in controlling this serious condition. Elimination of the rodents is not feasible, nor desirable, since it could lead to significant imbalances in the ecosystem.^{(3,27,28,34,43)}

The most effective way to decrease the risk of HCPS is to limit human exposure to infected rodents or to closed sites where there might be active infestation by these animals. In 2000, the CDC published detailed directives for the control of infestation by rodents and of the disease.⁽⁴³⁾ The publication contains specific orientation for prevention of contact with rodents, for the elimination of infestation by these animals and for the cleaning of areas where there are dead rodents or rodent feces, as well as for working in places where there have been confirmed infections or severe rodent infestations.⁽⁴³⁾

Peridomestic exposure merits special attention and can be avoided by cleaning the house and environs, by makes houses rodent proof, by sealing of cracks around doors, pipes and electrical conduits larger than 6 mm in diameter.

In general, rodent infestation is suspected after direct observation of the animals, finding nests or feces (these are small, dark and oval-shaped, resembling rice grains) or discovering bite marks on food and other objects.^{(27,28,32–34,43)}

In the areas where cases have been reported, the population should be educated in how to clean and handle excreta and dead rodents. Before entering infested places, it is advisable to ventilate the space for a few hours. The excreta should not be swept or vacuumed, for this would cause a grater aerosolization of particles.^(3,34,43)

It is also important to orient the population about recreational exposure to rodents, especially in camping, excursions and rural activities. A person should not sleep outdoors or on grass without ground protectors and tents. The garbage should be kept in closed bins and away from the tent. Food should be kept inside sealed containers so as not to attract rodents.^(18,43)

In houses located in infested areas, it is important to always keep sinks and plates clean, to discard garbage in closed containers and to keep boxes, clothes and other objects away from contact with the ground, to avoid rats nesting there. ⁽⁴³⁾

In rural houses, it is interesting the orientation on care with the storage of animal food and water, not keeping them available during the night. Every source of food for the rodents should be removed from the vicinity of the residence, as should abandoned vehicles, old tires, etc., which can serve as nests. Areas such as orchards, animal houses, as well as logs, bricks, stones and other materials should remain at least 50 meters distant from the house. Storage areas, such as silos, should be frequently ventilated and sealed to prevent the entrance of rodents. Harvests should not be stored outdoors.^{(3,18,32–34,43)}

The use of traps and rat poison helps control the rodent population in infested areas. People should be taught how to disarm the traps by 1 week after catching the last rodent. To discard the traps and the caught animals, it is important to wear latex or vinyl gloves. Before collecting the material, the excreta and dead rodents should be soaked with sodium hypochlorite (1:10 solution, prepared on the day it is going to be used). Detergent solutions or those that are commonly used for cleaning can be used, since the viral particles have a lipid envelope and can be inactivated by these measures.

The collected material should be placed in doubled plastic bags and sealed. To discard the material, it should be buried in holes 70–90 cm deep, burned or placed in a closed receptacle appropriate for garbage collection.^(18,43)

In the areas infested by rodents, their natural predators, such as nonpoisonous snakes and owls, should be protected. In places with severe infestation, in addition to the measures described above, it is important to use protective goggles and high efficiency particulate filter masks. In areas with persistent infestations it is sometimes necessary to contact a professional who specializes in the control of pests and rodents.⁽⁴³⁾

In the western part of the USA, where fleas are a reservoir for the plague, it is important to use repellent on clothes, shoes and hands before setting any traps. ^{(18, 43)}

Recommendations for the control of rodents and of hantavirus infection are detailed and updated on the CDC website: All about hantavirus ⁽¹⁸⁾ and can be obtained through contact with the CDC, National Center for Infectious Diseases (NCID), Special Pathogens Branch, email: [e-mail].

It is interesting to emphasize the possibility of interpersonal transmission of the Andes-like viruses, and precautions such as respiratory and general isolation in the care of those patients, besides universal measures in the control of infections, should be instituted.

Epidemiological Vigilance

Hantavirus infection is suspected when a fever is followed by acute respiratory distress syndrome (ARDS) in the absence of predisposing factors. Fever accompanied by radiology-proven evolution of bilateral infiltrates and need for oxygen supplementation is also indicative of HCPS. An HCPS pathogenesis should be considered when noncardiogenic pulmonary edema is observed at autopsy or when there is no specific identifiable cause of death.^{(3,18,27,43,61)}

In areas where there are confirmed cases of HCPS, vigilance can be increased with tests on cases of fever with mild pulmonary involvement or with renal disease and other fever-related conditions.⁽⁶¹⁾

Care in the transport of laboratory samples should be taken, using unbreakable containers to avoid inadvertent exposure. It is also important, during the transport, to clearly label the contents as contaminated biological material.⁽⁴³⁾

Epidemiological and serological surveys of captured rodents have been performed with the objective of determining which viral species are responsible for HCPS and identifying their rodent hosts.^{(27,28,43,61)}

Notifications

In Brazil, suspected cases of HCPS should be reported to the Epidemiological Vigilance Department of the city in which they occurred. Periodical epidemiological reports are provided by FUNASA. The virology laboratories, licensed for the diagnosis of hantavirus infection are : Instituto Adolfo Lutz, in São Paulo, SP (tel. [phone]) and the Institute Evandro Chagas, in Belém, PA. However, as the numbers of reported cases increase and we become aware that hantavirus is common in our country, it would be interesting to have a greater number of laboratories capable of making this diagnosis.

In the USA, the CDC periodically updates the epidemiological HCPS data on their Internet site (www.cdc.gov/ncidod/disease/hanta/hps/index/htm).

Perspectives

Recently, Hooper et al. developed an animal model of HCPS causing lethal disease by inoculating the Andes virus into a kind of hamster known as a Syrian hamster. The disease characteristics in the hamsters, including incubation period, fast and progressive evolution to respiratory failure and the pathological findings of pulmonary edema and pleura effusion are very similar to that of HCPS in humans.⁽⁷⁸⁾ The animal model creates perspectives for increased understanding of the physiopathology and immunomodulation of the disease, and therefore for the control of the attendant pulmonary edema and shock. Development of vaccines is also facilitated by studies using animal models. ^{(78, 79)}

Keeping in mind the mechanisms of viral pathogenesis, another important issue to be studied is the determination of the protein for viral binding and the development of antibodies which recognize this protein and block its interaction with the integrins.⁽⁷⁹⁾

Since immunological mechanisms predominate in the pathogenesis of the disease, administration of monoclonal antibodies or of neutralizing antibodies obtained from the serum of recovering patients show some promise and are currently being evaluated.^(18,80)

Conclusion

As has been recently described, HCPS is still under investigation, which, in light of its extensive geographical distribution and incidence, make us suppose that this disease is still little recognized and diagnosed among us.^{(31-34,42,48)}

The Juquitiba, Araraquara and Castelo dos Sonhos viruses have been implicated in HCPS in Brazil. This is a novel disease that merits further studies that would take into account the milder cases of the disease, the cases with fever and renal involvement and the pediatric aspects of the disease. There is no assurance that interpersonal transmission does not occur, and therefore respiratory and general isolation measures should be used in the presence of suspected cases.^{(18,27,43,61)}

It is important to point out that, due to its nonspecific prodromes and deadly clinical course, it is necessary that healthcare workers, especially Pulmonologists and intensivists, be aware of the prevalence of HCPS. Referral to tertiary care centers and the adoption of appropriate intensive care support measures will have a significant impact of the survival of these patients.

Acknowledgments

The authors would like to thank Carlos André Santos Pincelli, for revising the manuscript and Dr. Rodrigo F. Reiff for the help with the photographic material.

References

Submitted: 25/04/2003. Accepted, after revision: 11/06/2003.

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*

Research performed in the Pulmonology Department – University of São Paulo School of Medicine, São Paulo, SP.

Publication Dates

• Publication in this collection
  02 Mar 2004
• Date of issue
  Oct 2003

History

• Accepted
  11 June 2003
• Received
  25 Apr 2003