Correspondence
Hantavirus Pulmonary Syndrome in New England and Europe
N Engl J Med 1994; 331:545-548August 25, 1994
- Article
To the Editor:
The hantavirus pulmonary syndrome, first described in June 1993, was initially thought to be limited to the western United States. More recently, there have been cases reported in Indiana and Louisiana1,2. We now report a case of the hantavirus pulmonary syndrome in New England.
A 22-year-old white man presented to a Rhode Island emergency room with a nonproductive cough and shaking chills. The patient had been seen two days earlier for symptoms of bilateral flank pain, chills, and mild abdominal pain, which were thought to be due to an acute viral syndrome. He had recently cleaned a warehouse in New York City and had had considerable exposure to dust.
The patient appeared lethargic and had tachypnea and circumoral and peripheral cyanosis. On physical examination, his temperature was 38.5 °C (101.4 °F), blood pressure 100/80 mm Hg, pulse 132 per minute, and respiratory rate 44 per minute, with bibasilar rales. With 100 percent double nebulizers, the arterial blood gas values were pH, 7.38; partial pressure of carbon dioxide, 30 mm Hg; and partial pressure of oxygen, 64 mm Hg. The white-cell count was 7400 per cubic millimeter, with 31 percent neutrophils, 41 percent band forms, 17 percent lymphocytes, 5 percent monocytes, and 6 percent activated lymphocytes. The chest radiograph showed diffuse interstitial and alveolar infiltrates. Despite ventilatory support, the patient's oxygenation failed to improve. His condition deteriorated rapidly, and he died approximately five hours after his arrival at the emergency room. The autopsy report showed pulmonary edema, and the lung tissue was positive for hantavirus.
Hantavirus is an RNA virus that is endemic in wild rodent populations and is spread to humans by inhalation of aerosolized urine and feces from infected rodents3. The Muerto Canyon virus was the first pathogenic hantavirus discovered in the United States and was the cause of the outbreak of the hantavirus pulmonary syndrome in the Four Corners region of New Mexico, Arizona, Colorado, and Utah4. The reservoir of the virus, Peromyscus maniculatus, inhabits all areas of the United States except the Southeast and states along the Atlantic Coast5. Our patient had not traveled to areas where hantavirus infections had previously been reported. He presumably was exposed to the virus during his warehouse work in New York City. This documented case of the hantavirus pulmonary syndrome in New England makes it clear that this often fatal illness may not be limited to any particular region of the United States. Clinicians should consider this disease when a healthy adult who has been exposed to dust or rodent droppings presents with flulike symptoms that progress to respiratory failure.
5 ReferencesL. Ellen Brackett, M.D.
Joshua Rotenberg, B.A.
Charles B. Sherman, M.D., M.P.H.
Miriam Hospital, Providence, RI 029061
Slama TG ,Zon R . Fatal hantavirus pulmonary syndrome in Indiana. N Engl J Med 1994;330:1010-1010
Full Text | Web of Science | Medline2
Update: hantavirus disease -- United States, 1993
Medline3
Childs JE ,Kaufmann AF ,Peters CJ ,Ehrenberg RL . Hantavirus infection -- southwestern United States: interim recommendations for risk reduction. MMWR Morb Mortal Wkly Rep 1993;42:1-13
Medline4
Hantavirus pulmonary syndrome, United States 1993
CrossRef | Web of Science5
Stone R . The mouse-pinon nut connection. Science 1993;262:833-833
CrossRef | Web of Science | Medline
To the Editor:
In response to the report by Duchin et al. (April 7 issue),1 we wish to point out that the adult respiratory distress syndrome may also be encountered in the disease variant seen in Europe, epidemic nephritis, which is caused by the Puumala serotype of the hantavirus genus. This infection is spread by red bank voles. During the largest outbreak so far in Belgium,2 we registered a total of 51 cases, all confirmed by an enzyme-linked immunosorbent assay for anti-Puumala IgM antibodies. The immunofluorescent-antibody screening for IgG against Puumala serotype CG 18-20 showed a mean geometric titer of 989.1, which is significantly higher than that for the Hantaan species (72.5, P<0.001) or the Seoul species (48.8, P<0.001). Moreover, bank voles that were positive for Puumala antigen were captured in the areas where these patients lived2.
Including one previous patient, we now know of a total of seven patients who have presented with the noncardiogenic adult respiratory distress syndrome and this hantavirus infection (Table 1Table 1
Clinical and Laboratory Characteristics of Seven Patients with Puumala-Induced Epidemic Nephritis Complicated by Acute Lung Injury or the Adult Respiratory Distress Syndrome.). The course of disease was milder in these patients than in those described by Duchin et al. Only Patient 5 required mechanical ventilation. The course of disease in this patient was complicated by shock (blood pressure, 65/40 mm Hg), a low cardiac index (2.6 liters per minute per square meter of body-surface area, with a systemic vascular resistance of 1.229 dyn • sec • cm-5), disseminated intravascular coagulation, and acute renal failure. Severe adult respiratory distress syndrome developed (arterial oxygen saturation, 73 percent), with diffuse interstitial pulmonary infiltrates, again without signs of cardiac decompensation (pulmonary-capillary wedge pressure, 5 mm Hg; pulmonary-artery pressure, 14/8 mm Hg). After 20 days of mechanical ventilation he recovered without sequelae.In Belgium, a patient described in 1987 with epidemic nephritis had cough, bilateral interstitial infiltrates, hypoxemia (partial pressure of arterial oxygen, 62 mm Hg), and a restricted diffusion capacity of the lung (carbon monoxide diffusion capacity, 48 percent of the normal value)3. Of 19 Swedish patients with epidemic nephritis, 10 had pulmonary infiltrates or pleural effusions that were linked to the degree of inflammatory response4.
In all forms of hantavirus disease, the degree of systemic inflammatory response syndrome seems at least as important as the serotype in determining the final clinical symptoms, and the kidneys are not always the main target organs. In fact, patients with Puumala infections may present with few renal symptoms and mainly pulmonary symptoms,5 or they may even present with viral hepatitis (unpublished data). Epidemic adult respiratory distress syndrome has emerged recently in Brazil as a complication of leptospirosis, another zoonosis that produces the systemic inflammatory response syndrome and has many other striking similarities to hantavirus infection6.
6 ReferencesJ. Clement, M.D.
Military Hospital Queen Astrid, B-1120 Brussels, BelgiumP. Colson, M.D.
Centre de Sante des Fagnes, B-6460 Chimay, BelgiumP. McKenna, B.Sc., Ph.D.
Military Hospital Queen Astrid, B-1120 Brussels, Belgium1
Duchin JS ,Koster FT ,Peters CJ , et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N Engl J Med 1994;330:949-955
Full Text | Web of Science | Medline2
Clement J ,McKenna P ,Colson P , et al. Hantavirus epidemic in Europe, 1993. Lancet 1994;343:114-114
CrossRef | Web of Science | Medline3
Buysschaert M ,Pirson F ,Mendez Mayorga V ,Van der Groen G ,Coche E . Nephropathie a hantavirus en Belgique: description de 2 nouveaux cas originaires des provinces du Sud. Acta Clin Belg 1987;42:311-315
Web of Science | Medline4
Linderholm M ,Billstrom A ,Settergren B ,Tarnvik A . Pulmonary involvement in nephropathia epidemica as demonstrated by computed tomography. Infection 1992;20:263-266
CrossRef | Web of Science | Medline5
Alexeyev OA ,Baranov BA . Puumala virus infection without signs of renal involvement. Scand J Infect Dis 1993;25:525-527
CrossRef | Web of Science | Medline6
Goncalves AJ ,de Carvalho JE ,Guedes-e-Silva JB ,Rozembaum R ,Vieira AR . Hemoptises e sindrome de angustia respiratoria do adulto como causas de morte na leptospirose: mudancas de padroes clinicos e anatomopatologicos. Rev Soc Bras Med Trop 1992;25:261-270
Medline
To the Editor:
We analyzed data released by the Centers for Disease Control and Prevention (CDC) on the hantavirus pulmonary syndrome in the Four Corners area and found discrepancies in the case numbers for patients presenting with unexplained adult respiratory distress syndrome and for those with confirmed hantavirus infection. In July 1993, 18 cases were positive for hantavirus and 28 were under investigation1. The number of cases that were negative for hantavirus was not reported. By January 1994, hantavirus infection had been confirmed in 25 cases reported during the period from April through July 19932. From this information, it appears that 21 of 28 cases (75 percent) under investigation in July 1993 were not positive for hantavirus and were therefore eliminated from the total count. Since the total percentage of cases that were negative for hantavirus has not been disclosed, the prevalence of hantavirus among these cases is unknown.
We question the role of hantavirus in the disease outbreak3. The evidence in support of hantavirus includes a polymerase-chain-reaction analysis in which trace amounts of viral genetic material can be greatly amplified to permit detection, rising antibody titers to hantavirus in a few cases, and unpublished data on the immunohistochemical detection of hantavirus in tissue specimens4,5. However, the virus in patients with the hantavirus pulmonary syndrome has not been quantified, and it is not known whether the virus is present in quantities that are consistent with those of an agent causing disease. Also, the frequency of hantavirus infection among healthy people in the area of the outbreak has not been thoroughly assessed.
Laboratory studies suggesting the presence of hantavirus do not prove causality. The presence of hantavirus may reflect an opportunistic infection or a benign infection unrelated to the pulmonary disease. Regardless of whether hantavirus is the etiologic agent of the hantavirus pulmonary syndrome, a large number of cases in the outbreak were not associated with hantavirus and remain unexplained.
5 ReferencesTina Harrach Denetclaw, Pharm.D.
Wilfred F. Denetclaw, Jr., Ph.D.
University of California, Berkeley, CA 947201
Update: hantavirus disease -- southwestern United States, 1993
Medline2
Hantavirus pulmonary syndrome -- United States, 1993
Medline3
Denetclaw WF Jr ,Denetclaw TH . Is “south-west US mystery disease” caused by hantavirus? Lancet 1994;343:53-54
CrossRef | Web of Science | Medline4
Nichol ST ,Spiropoulou CF ,Morzunov S , et al. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914-917
CrossRef | Web of Science | Medline5
Duchin JS ,Koster FT ,Peters CJ , et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N Engl J Med 1994;330:949-955
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The letter by Brackett et al. illustrates the increasing geographic scope of the hantavirus pulmonary syndrome in the United States. Additional hantaviruses causing the syndrome outside the range of the deer mouse are being recognized1. However, the exact location where the patient described by Brackett et al. acquired the infection is not known. We agree that clinicians should consider the hantavirus pulmonary syndrome in patients with a febrile prodrome followed by acute respiratory illness.
Clement et al. document 1 patient in 51 with acute Puumala virus infection and epidemic nephritis who had severe pulmonary involvement. This is consistent with reports of pulmonary manifestations in a small proportion of patients with Hantaan virus infection, usually as a complication of acute renal failure2. Unlike the cases described by Clement et al., cases of the hantavirus pulmonary syndrome have been characterized by severe pulmonary manifestations in the absence of acute renal failure. We believe that the extensive clinical differences between the hantavirus pulmonary syndrome and epidemic nephritis reflect differences in the pathogenesis of infection by the causative viruses, not in the degree of systemic inflammatory response.
Denetclaw and Denetclaw are correct in asserting that in 75 percent of the cases under investigation for the hantavirus pulmonary syndrome through January 1994, either the laboratory evaluation was negative or no specimens were available for testing. We maximized the sensitivity of our clinical case definition by using broad criteria (unexplained bilateral interstitial infiltrates on the chest roentgenogram and arterial oxygen saturation <90 percent); cases were then confirmed with the use of highly specific laboratory tests. We established the cause of the hantavirus pulmonary syndrome by testing for an acute immune response to hantavirus antigens and for hantavirus genome in tissue specimens3. In addition, immunohistochemical studies revealed hantavirus antigens in the endothelial cells of multiple organs, particularly the lungs. For all cases in which more than one test was used, the results were concordant, and polymerase-chain-reaction and immunohistochemical tests performed on control tissue specimens were uniformly negative4.
Some patients identified by our broad clinical case definition who had negative tests for hantavirus infection probably had other illnesses, such as community-acquired pneumonia, the causes of which remain unidentified in nearly half the cases5. Without data on the background incidence of the adult respiratory distress syndrome of unknown cause, we cannot determine whether cases of the syndrome due to other causes increased during the period of the outbreak.
Evidence of hantavirus infection among healthy people in the area of the outbreak is uncommon. Among over 500 residents of the Four Corners states who were asymptomatic or had mild illnesses, the seropositivity rate was 1 percent; none of the people had evidence of acute infection (CDC: unpublished data).
5 ReferencesJeffrey S. Duchin, M.D.
Robert F. Breiman, M.D.
Jay C. Butler, M.D.
C.J. Peters, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333Frederick T. Koster, M.D.
University of New Mexico Hospital, Albuquerque, NM 871311
Newly identified hantavirus -- Florida, 1994MMWR Morb Mortal Wkly Rep 1994;43:99-105
Medline2
Giles RB ,Sheedy JA ,Ekman CN , et al. The sequelae of epidemic hemorrhagic fever: with a note on causes of death. Am J Med 1954;16:629-638
CrossRef | Web of Science | Medline3
Nichol ST ,Spiropoulou CF ,Morzunov S , et al. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914-917
CrossRef | Web of Science | Medline4
Ksiazek TG, Peters CJ, Rollin PE, et al. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg (in press).
5
Marrie TJ . Community-acquired pneumonia. Clin Infect Dis 1994;18:501-515
CrossRef | Web of Science | Medline
Author/Editor Response
The case report by Brackett et al. highlights the need to consider hantavirus infection in the differential diagnosis of unexplained cases of the adult respiratory distress syndrome anywhere in the United States. Their patient in Rhode Island presented with all four components of the systemic inflammatory response syndrome: fever, tachycardia, tachypnea, and high or low white-cell counts or over 10 percent band forms. I suggested in my editorial (April 7 issue)1 that this constellation of findings is a sensitive marker and may be predictive of the hantavirus pulmonary syndrome.
Clement et al. correctly point out that the adult respiratory distress syndrome may occur uncommonly with other infectious agents, including the European hantavirus, Puumala virus. It is interesting that their case series was derived from an outbreak. Variation in the incidence rates of Puumala virus infection in Sweden corresponds well with the cyclic variation in the prevalence of the rodent host, the riverbank vole2. Epidemics occur with increases in the population of the rodent host, whereas sporadic infection relates to the lower background prevalence of riverbank voles.
The parallel in the United States is obvious. The epidemic of the hantavirus pulmonary syndrome in the Southwest was identified in association with a 10-fold increase in the prevalence of the local rodent host, the deer mouse3. We should anticipate sporadic cases of the hantavirus pulmonary syndrome as the prevalence of deer mice falls to background levels. Clinically, it is interesting to note that the patients in Belgium who had Puumala virus infection and the adult respiratory distress syndrome, described by Clement et al., were older (median age, 61 years) than those in the United States with Muerto Canyon virus infection (mean age, 32 years)4.
Denetclaw and Denetclaw offer an interesting challenge to the CDC to examine the relation between cause and effect when describing a new illness. Some of the patients in the southwestern United States who had adult respiratory infection may not have had evidence of prior infection with the Muerto Canyon virus. This could have resulted from infection or disease due to other causes or from the insensitivity of tests for the Muerto Canyon virus. It is also true that not all of Koch's postulates have been fulfilled. Nevertheless, there is the polymerase-chain-reaction analysis showing hantavirus-specific RNA in tissue specimens from the patients, the presence of both IgM antibody tests and rising antibody titers to hantavirus, the presence of hantavirus antigen in capillary endothelium from the patients, the epidemiologic data showing the exposure of the patients to deer mice and evidence of hantavirus infection in the deer mice, the isolation of the hantavirus from deer mice, and analogies to infection with other hantavirus agents. Together, these findings are compelling evidence for a true cause-effect relation.
4 ReferencesRichard P. Wenzel, M.D.
University of Iowa College of Medicine, Iowa City, IA 522421
Wenzel RP . A new hantavirus infection in North America. N Engl J Med 1994;330:1004-1005
Full Text | Web of Science | Medline2
Settergren B ,Juto P ,Wadell G ,Trollfors B ,Norrby SR . Incidence and geographic distribution of serologically verified cases of nephropathia epidemica in Sweden. Am J Epidemiol 1988;127:801-807
Web of Science | Medline3
Stone R . The mouse-pinon nut connection. Science 1993;262:833-833
CrossRef | Web of Science | Medline4
Duchin JF ,Koster FT ,Peters CJ , et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. N Engl J Med 1994;330:949-955
Full Text | Web of Science | Medline
- Citing Articles (25)
Citing Articles
1
J. Clement, P. Maes, K. Lagrou, M. Ranst, N. Lameire. (2011) A unifying hypothesis and a single name for a complex globally emerging infection: hantavirus disease. European Journal of Clinical Microbiology & Infectious Diseases
CrossRef2
J. P. CLEMENT, N. S. CROWCROFT, P. MAES, F. VAN LOOCK, P. COLSON, M. VAN RANST. (2011) Smoking and other risk factors for hantavirus infections: the whole story. Epidemiology and Infection 139:08, 1284-1286
CrossRef3
Antti Paakkala, Ritva Järvenpää, Satu Mäkelä, Heini Huhtala, Jukka Mustonen. (2011) Pulmonary high-resolution computed tomography findings in nephropathia epidemica. European Journal of Radiology
CrossRef4
Jussi Sane, Outi Laine, Satu Mäkelä, Antti Paakkala, Hanna Jarva, Jukka Mustonen, Olli Vapalahti, Seppo Meri, Antti Vaheri. (2011) Complement activation in Puumala hantavirus infection correlates with disease severity. Annals of Medicine1-8
CrossRef5
J. Rasmuson, C. Andersson, E. Norrman, M. Haney, M. Evander, C. Ahlm. (2011) Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. European Journal of Clinical Microbiology & Infectious Diseases
CrossRef6
Outi Laine, Satu Mäkelä, Jukka Mustonen, Heini Huhtala, Timea Szanto, Antti Vaheri, Riitta Lassila, Lotta Joutsi-Korhonen. (2010) Enhanced thrombin formation and fibrinolysis during acute Puumala hantavirus infection. Thrombosis Research 126:2, 154-158
CrossRef7
J. Clement, P. Maes, C. van Ypersele de Strihou, G. van der Groen, J. M. Barrios, W. W. Verstraeten, M. van Ranst. (2010) Beechnuts and outbreaks of nephropathia epidemica (NE): of mast, mice and men. Nephrology Dialysis Transplantation 25:6, 1740-1746
CrossRef8
Piet Maes, Jan Clement, Marc Van Ranst. (2009) Recent approaches in hantavirus vaccine development. Expert Review of Vaccines 8:1, 67-76
CrossRef9
J. Clement, P. Maes, G. Ducoffre, F. Van Loock, M. van Ranst. (2008) Hantaviruses: Underestimated Respiratory Viruses?. Clinical Infectious Diseases 46:3, 477-479
CrossRef10
E. Seitsonen, M. Hynninen, E. Kolho, H. Kallio-Kokko, V. Pettilä. (2006) Corticosteroids combined with continuous veno-venous hemodiafiltration for treatment of hantavirus pulmonary syndrome caused by Puumala virus infection. European Journal of Clinical Microbiology & Infectious Diseases 25:4, 261-266
CrossRef11
Piet Maes, Jan Clement, Irina Gavrilovskaya, Marc Van Ranst. (2004) Hantaviruses: Immunology, Treatment, and Prevention. Viral Immunology 17:4, 481-497
CrossRef12
E. Keyaerts, E. Ghijsels, P. Lemey, P. Maes, P. Zachee, R. Daelemans, T. Vervoort, G. Mertens, M. Van Ranst, J. Clement. (2004) Plasma Exchange--Associated Immunoglobulin M--Negative Hantavirus Disease after a Camping Holiday in Southern France. Clinical Infectious Diseases 38:10, 1350-1356
CrossRef13
Pietro Caramello, Francesca Canta, Lodovica Bonino, Corrado Moiraghi, Fabrizia Navone, Filippo Lipani, Rosanna Balbiano, Anna Maria Caputo, Valerio Gai. (2002) Puumala Virus Pulmonary Syndrome in a Romanian Immigrant. Journal of Travel Medicine 9:6, 326-329
CrossRef14
C. J. Peters, MD, Gary L. Simpson, MD, PhD, MPH, H. Levy, MD, PhD. (1999) SPECTRUM OF HANTAVIRUS INFECTION: Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome 1. Annual Review of Medicine 50:1, 531-545
CrossRef15
Moritz Vahlenkamp, Thomas Müller, Kirsten Tackmann, Ulf Löschner, Herbert Schmitz, Michael Schreiber. (1998) The muskrat (Ondatra zibethicus) as a new reservoir for puumala-like hantavirus strains in Europe. Virus Research 57:2, 139-150
CrossRef16
M. Kanerva, J. Mustonen, A. Vaheri. (1998) Pathogenesis of puumala and other hantavirus infections. Reviews in Medical Virology 8:2, 67-86
CrossRef17
Mark R. Crowley, Robert W. Katz, Randolph Kessler, Steven Q. Simpson, Howard Levy, Gustav W. Hallin, James Cappon, Jeffrey B. Krahling, Jorge Wernly. (1998) Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation. Critical Care Medicine 26:2, 409-414
CrossRef18
PierreE. Rollin, ThomasG. Ksiazek, SherifR. Zaki, StuartT. Nichol, C.J. Peters, Michael Schreiber, Thomas Laue, Carsten Wolff. (1996) Hantavirus pulmonary syndrome in Germany. The Lancet 347:9012, 1416-1417
CrossRef19
J. Clement, P. Heyman, P. Colson, P.H.P. Groeneveld. (1996) Spread of hantavirus infections in Europe. The Lancet 347:9003, 771
CrossRef20
Menelaos Papadimitriou. (1995) Hantavirus nephropathy. Kidney International 48:3, 887-902
CrossRef21
Brian Hjelle, John Krolikowski, Norah Torrez-Martinez, Francesca Chavez-Giles, Cynthia Vanner, Elizabeth Laposata. (1995) Phylogenetically distinct hantavirus implicated in a case of hantavirus pulmonary syndrome in the Northeastern United States. Journal of Medical Virology 46:1, 21-27
CrossRef22
(1995) More on Hantavirus in New England and New York. New England Journal of Medicine 332:5, 337-338
Full Text23
Paul H. P. Groeneveld, Paul Colson, Kitty M. C. Kwappenberg, Jan Clement. (1995) Increased Production of Nitric Oxide in Patients Infected with the European Variant of Hantavirus. Scandinavian Journal of Infectious Diseases 27:5, 453-456
CrossRef24
Jin-Won Song, Luck-Ju Baek, D.Carleton Gajdusek, Richard Yanagihara, Irina Gavrilovskaya, BenjaminJ Luft, ErichR Mackow, Brian Hjelle. (1994) Isolation of pathogenic hantavirus from white-footed mouse (Peromyscus leucopus). The Lancet 344:8937, 1637
CrossRef25
Lalit Dar, Rajeev Thakur, VeenitaS. Dar, T.Jacob John. (1994) India: is it plague?. The Lancet 344:8933, 1359-1360
CrossRef
- Letters
