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UNDIAGNOSED PULMONARY DISEASE - INDIA (02): HANTAVIRUS NEPHROPATHY
************************************************** ****************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>
Date: Fri 8 Aug 2008
From: Jan Clement and Piet Maes, Hantavirus Reference Centre, Leuven, Belgium
<Jan.Clement@uz.kuleuven.ac.be>
Hantaviruses in India
---------------------
Even if the Uttarakhand cases were serologically to be confirmed in
Pune and/or New Delhi as recent hantavirus infections, and
consequently could be presented eventually as "Hantavirus Pulmonary
Syndrome (HPS)" cases, they would not be, as stated by the local
health authorities, the 1st to be reported so in India. We briefly
reported already in 2000 2 fatal hantavirus cases in South India:
see, Clement J., Muthusethupathi M., Nainan G.,Van Ranst M. "First
fatal cases of hantavirus nephropathy in India". Clin Inf Dis 2000; 31: 315.
As discussed in a subsequent 2006 publication, one of these acute
Indian fatalities had all the clinical characteristics of severe HPS,
also complicated however with renal involvement: see, Clement J, Maes
P, Muthusethupathi M, Nainan G, Van Ranst M. "First evidence of fatal
hantavirus nephropathy in India, mimicking leptospirosis." Nephrol
Dial Transpl 2006; 21: 826-7:
<http://ndt.oxfordjournals.org/cgi/content/full/21/3/826?etoc>.
Since until recently no clinical hantavirus infections had been
documented in India, we screened acute Indian cases from Chennai and
Cochin (South India), suspected for leptospirosis, by means of
recombinant nucleoprotein ELISA for Puumala virus (PUUV) and SIA
(strip immunoblot assay) with recombinant PUUV and Seoul virus (SEOV)
antigens. Leptospirosis was used as clinical screening symptom,
because fever, myalgiae and acute renal failure (ARF) in
leptospirosis are indistinguishable from the clinical symptoms of
"Hemorrhagic Fever with Renal Syndrome"(HFRS) in the Old World
hantavirus infections. More importantly, cases in both diseases often
mention previous rodent contacts. PUUV was chosen as screening agent
because it is the most important hantavirus in Europe and Russia.
SEOV was added because it is spread by wild rats (_Rattus rattus_ and
_R. norvegicus_), the only known so far rodent reservoir of
hantavirus with a documented presence in India.
All studied sera were seronegative for leptospirosis in MAT and
Patoc- IgG and IgM ELISA. Dengue infection was likewise serologically
excluded. However, we found positive (PUUV and/or SEOV) IgG SIA in
10/60 cases. All IgG SIA-positive cases, except 1 SEOV, were also IgM
SIA-positive, and were confirmed by positive IgM ELISA. 2 of the 10
Indian cases were fatal. One Chennai patient with dyspnoea died of
ARF despite peritoneal dialysis. The 2nd fatal case was a Cochin
female patient (64 years old), who presented with fever, myalgiae,
abdominal pain, and severe dyspnoea; i.e., with symptoms similar to
the current Uttarakhand cases. She developed jaundice, very low
platelets (7000/mm [cubed]), disseminated intravascular coagulation
(DIC), and ARF needing dialysis as well. Moreover, an adult
respiratory distress syndrome (ARDS) or a HPS picture with extreme
hypoxia developed, prompting not only dialysis for fluid removal, but
additionally also mechanical ventilation, as indicated in other
severe HPS cases. Despite this intensive care treatment, the patient
died in refractory shock on hospital day 7. SIA IgG and IgM was
clearly positive for PUUV-bands, and PUUV IgM was likewise positive
in ELISA, thus confirming for the 1st time and in 2 different test
formats a recent and fatal hantaviral infection in an Indian patient.
In a 2nd step, we applied RT-PCR on all Indian sera, including the 2
fatal cases, with primers specific for most of hitherto known
hantaviral pathogens, being PUUV, SEOV, Hantaan virus (HTNV), Dobrava
virus (DOBV) and Andes virus (ANDV). All turned out to be negative.
Moreover, we also performed RT-PCR for Thottapalayam virus (TPMV),
which was equally negative. TPMV is the only indigenous hantavirus
known in India, since it was isolated already in 1964 from a house
shrew (_Suncus murinus_) captured in Thottapalayam, near Vellore in
South India. No human TPMV pathogenicity has been demonstrated so
far, and it should be noted that shrews are insectivores, not
rodents. So far, human hantavirus pathogenicity has been linked to
rodents only.
As explained in a Letter to the Indian Journal of Medical Research
(Clement J, Maes P, Van Ranst M. "Which hantaviruses in India?"
Indian J Med Res. 2006; 123: 91-2.), our SEOV-positive results could
be expected, and SEOV-induced ARF might be considered indeed in the
differential diagnosis of leptospirosis in India, as elsewhere in the
world, since the wild rat is the only cosmopolitan hantavirus
reservoir. However, the PUUV-positive results came as a surprise,
particularly in the 2 fatal Indian cases. In Europe and Russia, PUUV
infections are spread by bank voles (_Myodes glareolus_), but this
rodent is absent from India, as are all other related species of the
subfamily _Arvicolinae_. Consequently, PUUV cannot be expected to be
endemic in India. Bearing in mind also our PCR-negative findings,
serological results in India, positive for PUUV (and even more
specific techniques such as SIA), should be interpreted as
cross-reactions with another yet unknown, but PUUV- like hantavirus
strain. Cross-reactions with TPMV are unlikely, since this
insectivore-borne hantavirus is genetically totally different from
all other known rodent-borne hantaviruses. Moreover, we recently
demonstrated a similar PUUV-like IgG and IgM seroreaction in acute
leptospirosis-suspected cases from Sri-Lanka, some of which also
presented with cough or dyspnea (manuscript in preparation, and see
Promed-mail 20080606.1808 "Leptospirosis- Sri Lanka (02): Hantavirus
also suspected").
Sri-Lanka is a country neighbouring India, with a fauna very similar
to it, including the total absence of rodent species of the subfamily
_Arvicolinae_. Interestingly, it should be remembered that Sin Nombre
virus (SNV), and Andes virus (ANDV), the 2 main etiologic factors of
HPS in the New World, are genetically related to PUUV (as are their
rodent reservoirs), thus explaining frequent cross-reactions in
serology. In fact, it was a PUUV-like reaction in ELISA on the sera
of the 1st HPS cases from the Four Corners region in the USA that
ultimately led to the discovery in 1993 of a new highly fatal
pathogen, affecting mainly (but not only) the lungs.
From a purely clinical point of view, it is unlikely that the severe
hospital course as depicted above in the fatal Cochin case could be
attributed to a true PUVV infection, which is mostly rather mild or
even asymptomatic (Clement J, Maes P, Van Ranst M. Acute Kidney
Injury in emerging, non-tropical Infections. Acta Clin Belg
2007;62:387-95). In fact, and as pointed out already in 2006, [the
patient's] course with ARF, DIC, ARDS, and refractory shock leading
to death one week after admission is highly reminiscent of the more
severe American HPS forms. As we now realize, renal participation is
more and more noted together with lung symptoms in HPS, particularly
in South American ANDV-induced forms. Conversely, severe
non-cardiogenic acute lung edema, i.e., a HPS-like complication, has
been reported in Old World HFRS as well, including PUUV infections
(Clement J., Colson P., Mc Kenna P. Hantavirus pulmonary syndrome in
New England and Europe. N.Eng.J.Med. 1994; 331: 545-6.
(see: <http://content.nejm.org/cgi/content/full/331/8/545?
ijkey=0e4b01144fe8ff212d732a17c71e293434a7d8be&key type2=tf_ipsecsha>
[subscription required]).
For comparison with the current Uttarakhand cases we need more
clinical details indeed, which can be readily available, such as the
presence or absence of initial thrombocytopenia and proteinuria, of
leukocytosis with a left shift, and of immunoblasts.
--
Jan Clement MD and Piet Maes PhD
Hantavirus Reference Centre
Laboratory of Clinical and Epidemiological Virology,
Department of Microbiology and Immunology,
Rega Institute and Universitary Hospitals Leuven,
Kapucijnenvoer 33,
BE-3000 Leuven
BELGIUM
<Jan.Clement@uz.kuleuven.ac.be>
[This contribution is an authoritative statement of some significant
observations that have identified the existence of a novel hantavirus
in India which has been associated with HPS with renal involvement.
The agent resembles the rodent-associated hantaviruses such as the
European/Russian Puumala virus and the more cosmopolitan Seoul virus,
but not with Thottapalayam virus the only hantavirus so far isolated
in India which is transmitted by insectivores and not associated with
human disease.
The putative Indian hantavirus previously implicated in 2 fatal cases
of HPS-like disease in India may or may not be the agent responsible
for the outbreak in Uttarakhan. However, at the very least hantavirus
infection should be considered in the differential diagnosis of
leptospirosis and pulmonary syndromes with renal involvement in India
and elsewhere in Asia.
Uttarakhand (also known as Uttar Anchal) is located in the north of
India sharing a border with China to the north, with Nepal to the
east, Uttar Pradesh to the south, and Himachal Pradesh to the west. A
map of India showing the locations of Uttarakhan, Chennai and Cochin,
can be found at
<http://www.lib.utexas.edu/maps/middle_east_and_asia/india_pol01.jpg>.
- Mod.CP]
[see also:
Undiagnosed pulmonary disease - India: RFI 20080807.2434
Leptospirosis - Sri Lanka (02): hantavirus also susp. 20080606.1808
2005
----
Hantavirus - India (02) 20051105.3240
Hantavirus - India 20051103.3213]
....................cp/ejp/mpp
-
-------
************************************************** ****************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>
Date: Fri 8 Aug 2008
From: Jan Clement and Piet Maes, Hantavirus Reference Centre, Leuven, Belgium
<Jan.Clement@uz.kuleuven.ac.be>
Hantaviruses in India
---------------------
Even if the Uttarakhand cases were serologically to be confirmed in
Pune and/or New Delhi as recent hantavirus infections, and
consequently could be presented eventually as "Hantavirus Pulmonary
Syndrome (HPS)" cases, they would not be, as stated by the local
health authorities, the 1st to be reported so in India. We briefly
reported already in 2000 2 fatal hantavirus cases in South India:
see, Clement J., Muthusethupathi M., Nainan G.,Van Ranst M. "First
fatal cases of hantavirus nephropathy in India". Clin Inf Dis 2000; 31: 315.
As discussed in a subsequent 2006 publication, one of these acute
Indian fatalities had all the clinical characteristics of severe HPS,
also complicated however with renal involvement: see, Clement J, Maes
P, Muthusethupathi M, Nainan G, Van Ranst M. "First evidence of fatal
hantavirus nephropathy in India, mimicking leptospirosis." Nephrol
Dial Transpl 2006; 21: 826-7:
<http://ndt.oxfordjournals.org/cgi/content/full/21/3/826?etoc>.
Since until recently no clinical hantavirus infections had been
documented in India, we screened acute Indian cases from Chennai and
Cochin (South India), suspected for leptospirosis, by means of
recombinant nucleoprotein ELISA for Puumala virus (PUUV) and SIA
(strip immunoblot assay) with recombinant PUUV and Seoul virus (SEOV)
antigens. Leptospirosis was used as clinical screening symptom,
because fever, myalgiae and acute renal failure (ARF) in
leptospirosis are indistinguishable from the clinical symptoms of
"Hemorrhagic Fever with Renal Syndrome"(HFRS) in the Old World
hantavirus infections. More importantly, cases in both diseases often
mention previous rodent contacts. PUUV was chosen as screening agent
because it is the most important hantavirus in Europe and Russia.
SEOV was added because it is spread by wild rats (_Rattus rattus_ and
_R. norvegicus_), the only known so far rodent reservoir of
hantavirus with a documented presence in India.
All studied sera were seronegative for leptospirosis in MAT and
Patoc- IgG and IgM ELISA. Dengue infection was likewise serologically
excluded. However, we found positive (PUUV and/or SEOV) IgG SIA in
10/60 cases. All IgG SIA-positive cases, except 1 SEOV, were also IgM
SIA-positive, and were confirmed by positive IgM ELISA. 2 of the 10
Indian cases were fatal. One Chennai patient with dyspnoea died of
ARF despite peritoneal dialysis. The 2nd fatal case was a Cochin
female patient (64 years old), who presented with fever, myalgiae,
abdominal pain, and severe dyspnoea; i.e., with symptoms similar to
the current Uttarakhand cases. She developed jaundice, very low
platelets (7000/mm [cubed]), disseminated intravascular coagulation
(DIC), and ARF needing dialysis as well. Moreover, an adult
respiratory distress syndrome (ARDS) or a HPS picture with extreme
hypoxia developed, prompting not only dialysis for fluid removal, but
additionally also mechanical ventilation, as indicated in other
severe HPS cases. Despite this intensive care treatment, the patient
died in refractory shock on hospital day 7. SIA IgG and IgM was
clearly positive for PUUV-bands, and PUUV IgM was likewise positive
in ELISA, thus confirming for the 1st time and in 2 different test
formats a recent and fatal hantaviral infection in an Indian patient.
In a 2nd step, we applied RT-PCR on all Indian sera, including the 2
fatal cases, with primers specific for most of hitherto known
hantaviral pathogens, being PUUV, SEOV, Hantaan virus (HTNV), Dobrava
virus (DOBV) and Andes virus (ANDV). All turned out to be negative.
Moreover, we also performed RT-PCR for Thottapalayam virus (TPMV),
which was equally negative. TPMV is the only indigenous hantavirus
known in India, since it was isolated already in 1964 from a house
shrew (_Suncus murinus_) captured in Thottapalayam, near Vellore in
South India. No human TPMV pathogenicity has been demonstrated so
far, and it should be noted that shrews are insectivores, not
rodents. So far, human hantavirus pathogenicity has been linked to
rodents only.
As explained in a Letter to the Indian Journal of Medical Research
(Clement J, Maes P, Van Ranst M. "Which hantaviruses in India?"
Indian J Med Res. 2006; 123: 91-2.), our SEOV-positive results could
be expected, and SEOV-induced ARF might be considered indeed in the
differential diagnosis of leptospirosis in India, as elsewhere in the
world, since the wild rat is the only cosmopolitan hantavirus
reservoir. However, the PUUV-positive results came as a surprise,
particularly in the 2 fatal Indian cases. In Europe and Russia, PUUV
infections are spread by bank voles (_Myodes glareolus_), but this
rodent is absent from India, as are all other related species of the
subfamily _Arvicolinae_. Consequently, PUUV cannot be expected to be
endemic in India. Bearing in mind also our PCR-negative findings,
serological results in India, positive for PUUV (and even more
specific techniques such as SIA), should be interpreted as
cross-reactions with another yet unknown, but PUUV- like hantavirus
strain. Cross-reactions with TPMV are unlikely, since this
insectivore-borne hantavirus is genetically totally different from
all other known rodent-borne hantaviruses. Moreover, we recently
demonstrated a similar PUUV-like IgG and IgM seroreaction in acute
leptospirosis-suspected cases from Sri-Lanka, some of which also
presented with cough or dyspnea (manuscript in preparation, and see
Promed-mail 20080606.1808 "Leptospirosis- Sri Lanka (02): Hantavirus
also suspected").
Sri-Lanka is a country neighbouring India, with a fauna very similar
to it, including the total absence of rodent species of the subfamily
_Arvicolinae_. Interestingly, it should be remembered that Sin Nombre
virus (SNV), and Andes virus (ANDV), the 2 main etiologic factors of
HPS in the New World, are genetically related to PUUV (as are their
rodent reservoirs), thus explaining frequent cross-reactions in
serology. In fact, it was a PUUV-like reaction in ELISA on the sera
of the 1st HPS cases from the Four Corners region in the USA that
ultimately led to the discovery in 1993 of a new highly fatal
pathogen, affecting mainly (but not only) the lungs.
From a purely clinical point of view, it is unlikely that the severe
hospital course as depicted above in the fatal Cochin case could be
attributed to a true PUVV infection, which is mostly rather mild or
even asymptomatic (Clement J, Maes P, Van Ranst M. Acute Kidney
Injury in emerging, non-tropical Infections. Acta Clin Belg
2007;62:387-95). In fact, and as pointed out already in 2006, [the
patient's] course with ARF, DIC, ARDS, and refractory shock leading
to death one week after admission is highly reminiscent of the more
severe American HPS forms. As we now realize, renal participation is
more and more noted together with lung symptoms in HPS, particularly
in South American ANDV-induced forms. Conversely, severe
non-cardiogenic acute lung edema, i.e., a HPS-like complication, has
been reported in Old World HFRS as well, including PUUV infections
(Clement J., Colson P., Mc Kenna P. Hantavirus pulmonary syndrome in
New England and Europe. N.Eng.J.Med. 1994; 331: 545-6.
(see: <http://content.nejm.org/cgi/content/full/331/8/545?
ijkey=0e4b01144fe8ff212d732a17c71e293434a7d8be&key type2=tf_ipsecsha>
[subscription required]).
For comparison with the current Uttarakhand cases we need more
clinical details indeed, which can be readily available, such as the
presence or absence of initial thrombocytopenia and proteinuria, of
leukocytosis with a left shift, and of immunoblasts.
--
Jan Clement MD and Piet Maes PhD
Hantavirus Reference Centre
Laboratory of Clinical and Epidemiological Virology,
Department of Microbiology and Immunology,
Rega Institute and Universitary Hospitals Leuven,
Kapucijnenvoer 33,
BE-3000 Leuven
BELGIUM
<Jan.Clement@uz.kuleuven.ac.be>
[This contribution is an authoritative statement of some significant
observations that have identified the existence of a novel hantavirus
in India which has been associated with HPS with renal involvement.
The agent resembles the rodent-associated hantaviruses such as the
European/Russian Puumala virus and the more cosmopolitan Seoul virus,
but not with Thottapalayam virus the only hantavirus so far isolated
in India which is transmitted by insectivores and not associated with
human disease.
The putative Indian hantavirus previously implicated in 2 fatal cases
of HPS-like disease in India may or may not be the agent responsible
for the outbreak in Uttarakhan. However, at the very least hantavirus
infection should be considered in the differential diagnosis of
leptospirosis and pulmonary syndromes with renal involvement in India
and elsewhere in Asia.
Uttarakhand (also known as Uttar Anchal) is located in the north of
India sharing a border with China to the north, with Nepal to the
east, Uttar Pradesh to the south, and Himachal Pradesh to the west. A
map of India showing the locations of Uttarakhan, Chennai and Cochin,
can be found at
<http://www.lib.utexas.edu/maps/middle_east_and_asia/india_pol01.jpg>.
- Mod.CP]
[see also:
Undiagnosed pulmonary disease - India: RFI 20080807.2434
Leptospirosis - Sri Lanka (02): hantavirus also susp. 20080606.1808
2005
----
Hantavirus - India (02) 20051105.3240
Hantavirus - India 20051103.3213]
....................cp/ejp/mpp
-
-------