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Cross Reactivity Observed in Patients Whose Blood Samples Tested Positive for Leptospira IgM and Dengue IgM Antibodies
Sushil Shah, Nilesh Shah

In modern times, when a patient presents with very high fever and toxicity, both the public and the medical practitioners become very alert to the diagnosis of either dengue or leptospirosis. And why not? Both are ‘killer’ diseases.
Metropolis Laboratory is one of the leading referral laboratories of the country having a chain of laboratories at Mumbai, Chennai, Jaipur, Cochin, Trichur and Dubai. The chain analyses over 10,000 tests per day. The laboratory is of an international standard and compares with the best in the world.

One of the aims of Metropolis Laboratory, which has a large number of medical staff, is to bring out any information which will help the clinicians.

We collected statistics of the blood samples sent to our laboratory during last one year.
Material and Results

Tables 1 and 6 show the results of these tests carried out in 4495 blood samples over the last one year in Mumbai (including suburbs).

TABLE 1
Levels of positivity
 
Total
Negative
%
Weakly Positive
%
Moderate
%
Strongly positive
%
Leptospira - IgM
1743
1227
71
243
14
182
10
91
5.3
Dengue - IgM
2752
1417
51.4
364
13.2
365
13
606
22
                   

TABLE 2
Statistical report + Dengue + Leptospira
  Total Samples Positive

Dengue-IgM+
Leptospira - IgM

733
Total patients tested for both
104
Positive for
both

TABLE 3
Statistical report - Dengue IgM + Leptospira IgM
Total patients for  
Dengue IgM/Leptospira IgM both 733
Patients positive for both 104
No of patients showed weak positive
for Dengue IgM
81
No of patients showed weak positive
for Leptospira IgM
102

TABLE 4
Urine Leptospira by DFM
Total patients tested 129
  Percentage
Positive 18
13.95
Negative 111 86.04
Patients registered for both urine leptospira and serum leptospira IgM
Total patients 31
Both positive 5
Only urine leptospira positive 10
Only leptospira IgM positive 12

TABLE 5
Zonewise incidence - positive
Test

Total +ve Sample

Zone code Zone Name Zone Desc Samples
Leptospira - IgM 481 007 Direct Direct 0
    1 Marine lines to Colaba (Ajay)
South Bombay 12
    2 Thane West
Central 5
    3 New Bombay Nerul Govandi
Central 34
    4 Ulhasnagar Ambernath Bada
Central 0
    5 Kalyan
Cental 4
    6 Thane — East
Central 16
    7 Mulund
Central 16
    8 Bhandup, Vikroli, Kanjurmarg
Cental 12
    9 Ghatkopar
Central 27
    10 Antophill, Sion, Chembur
Central 8
    11 Dadar, Matunga, Lalbaug, Lower Parel
Cental 15
    12 Virar
Western
11
    13 Dahisar, Miraroad
Western 7
    14 Bhayender
Western 8
    15 Kandivli - Borivli (East)
Western 4
    16 Kandivli - West
Western 2
    17 Malad
Western 4
    18 Goregaon
Western 6
    19 Andheri Jogeshwari
Western 31
    20 Andheri (W)
Western 21
    21 Vile-Parle
Western 6
    22 Santacruz
Western 28
    23 Bandra, Khar
Western 7
    24 Girgaon/Tardeo Opera H
Western 36
    25 Mahim/South Bombay
Western 1
    26 Dombivli
Western 20
    27 Kurla, Wadala
Western 3
    28 Mumbra/Airoli/Kalwa
Western 1
    29 Borivli-West
Western 21
    30 Colaba, Fort, Cuff P. Byculla
South Bombay 10
    31 Ghatkopar (W) and Kurla
Central 33
    32 Panvel, Nerul, Kopra, Kalamboli
New Bombay 18
    33 Pedder Road, Breach Candy,
South Bombay 27
    34 Jogeshwari
Western 6
    35 Goregaon Malad East
Western 4
 
OS Outstation Labs located outside 17

TABLE 6
Zonewise incidence - positive
Test

Total +ve Sample

Zone code Zone Name Zone Desc Samples
Leptospira - IgM 481 007 Direct Direct 21
    1 Marine lines to Colaba (Ajay)
South Bombay 3
    2 Thane West
Central 43
    3 New Bombay Nerul Govandi
Central 98
    4 Ulhasnagar Ambernath Bada
Central 6
    5 Kalyan
Cental 15
    6 Thane — East
Central 32
    7 Mulund
Central 71
    8 Bhandup, Vikroli, Kanjurmarg
Cental 38
    9 Ghatkopar
Central 77
    10 Antophill, Sion, Chembur
Central 24
    11 Dadar, Matunga, Lalbaug, Lower Parel
Cental 69
    12 Virar
Western
3
    13 Dahisar, Miraroad
Western 13
    14 Bhayender
Western 3
    15 Kandivli - Borivli (East)
Western 23
    16 Kandivli - West
Western 13
    17 Malad
Western 17
    18 Goregaon
Western 37
    19 Andheri Jogeshwari
Western 85
    20 Andheri (W)
Western 39
    21 Vile-Parle
Western 6
    22 Santacruz
Western 28
    23 Bandra, Khar
Western 17
    24 Girgaon/Tardeo Opera H
Western 53
    25 Mahim/South Bombay
Western 5
    26 Dombivli
Western 29
    27 Kurla, Wadala
Western 8
    28 Mumbra/Airoli/Kalwa
Western 3
    29 Borivli-West
Western 57
    30 Colaba, Fort, Cuff P. Byculla
South Bombay 5
    31 Ghatkopar (W) and Kurla
Central 30
    32 Panvel, Nerul, Kopra, Kalamboli
New Bombay 94
    33 Pedder Road, Breach Candy,
South Bombay 79
    34 Jogeshwari
Western 6
    35 Goregaon Malad East
Western 36
 
OS Outstation Labs located outside 61


Discussion
Dengue is a deadly virus, which is found in many parts of the world. Patients of dengue having haemorrhagic variety, if diagnosed in time, and then treated in an intensive care unit, the mortality rate can be reduced to even 1%. Leptospirosis is due to leptospira-spirochaete. In the past, it was thought that this disease is uncommon and occurs only in sewage workers or workers coming in contact with rats. Now we know that leptospira are often transmitted to humans by the ingestion of food and drink contaminated by the urine of the reservoir animal.

Our results show that both the illnesses are not uncommon in Mumbai and suburbs. 1335 blood samples were positive for dengue IgM antibodies. Elisa test for dengue IgM is very helpful, though not diagnostic in the evaluation of the cause of fever. Out of these, 606 blood samples tested strongly positive.

Regarding leptospirosis, though it was found to be not as common as dengue, we found leptospira IgM antibodies in 516 blood samples. In 91 patients, the test was strongly positive.

Table 4 shows that out of 129 patients, who were also referred for urine test for leptospira, this test was positive, only in 18 patients. Similarly, out of 31 patients referred for urine and serum leptospira, only 5 tested positive for both.
Though demonstration of leptospira by dark field examination is very specific and diagnostic, unfortunately, there is a lot of observer error and it depends on the person conducting the test. Neither do many doctors ask for urine and blood tests for dark field examination for spirochaetes.

Therefore, all over the world and in all textbooks, serological tests like IgM test for antibodies for leptospira have been recommended as one of the best investigations for diagnosis of leptospirosis. The sensitivity reported is around 93% or more. Regarding the diagnosis of Dengue, although the presence of virus in the blood would be the final word in the diagnosis, in practice, demonstration of the Dengue IgM antibodies is enough for diagnosis, since the demonstration of the virus is extremely difficult.

Our experience in the above cases has brought out the following facts, which may be helpful to clinicians:-
1. Both the illnesses are quite common in Mumbai city as well as the suburbs unlike the experience in other Indian cities1,2
2. Although the mosquitoes (responsible for transmitting dengue fever) and the leptospira are thought to be much more in suburbs and New Bombay as compared to Mumbai, it is interesting to note that both the diseases were as common in South Mumbai (‘D’ ward, the most aristocratic area of Bombay, which includes Pedder Road and Breach Candy). Even at present, many authorities are still under the false impression that the disease occurs in slum areas because of poor sanitation, open drainage and low socio-economic strata.1
3. What has been observed by us and perhaps reported for the first time in world literature is that we found 104 blood samples, where Elisa test for IgM antibodies was positive, for both the illnesses. The fact that the clinicians sent 733 samples for both the illnesses shows that clinically, they could not differentiate between the two illnesses.
Although in world literature, the sensitivity of both the tests has been shown to be more than 93%, from our results, it appears that the specificity of this test is much poorer and the test can now be compared to a test like IHa test for amoebiasis (Indirect haemagglutination test).

Talking about the sensitivity of the Elisa test, even in patients, who test weakly positive and are suffering from the above illnesses, it will be found that after a week, the blood sample becomes strongly positive. Thus even a weakly positive test is important. However, many weakly positive tests could be due to cross reactivity and thus falsely positive.
But what is more important to note is that in the absence of demonstration of the virus or leptospira or PCR, these tests are not 100% diagnostic. At present, this test is very easy to perform and is a very good routine test to screen off the above two illnesses. With the sensitivity of this test being so high, a negative test will certainly help the family physician to exclude these illnesses and remove the panic caused in the minds of relatives of patients, who have recently been reading so much about these illnesses in the newspapers - indeed, the illnesses which are deadly!
What is the likely explanation of the above cross reactivity? A possible explanation is that when a patient suffers from one of these two infections, IgM antibodies are formed, which could remain in the blood for a long time. The second possibility is the poor specificity of the reagents used.

SUMMARY
Perhaps for the first time in the world literature, we have observed cross reactivity in blood samples which tested positive for leptospira IgM and Dengue IgM antibodies.

REFERENCES
1. Kaur IR, Sachdeva R, Arora V, Talwar V. Preliminary Survey of Leptospirosis amongst febrile patients from Urban Slums of East Delhi. JAPI 2003; 51 : 249.
2. Sandhya A Kamath, Shashank R Joshi. Re-emerging of infections in Urban India - Focus Leptospirosis. JAPI 2003; 51 : 247.

LOW-DOSE BUDESONIDE FOR ASTHMA
Romain Pauwels and colleagues report results from a study in which patients with mild persistent asthma for less than 2 years, and not taking a glucocorticoid regularly, were given low-dose budesonide or placebo for 3 years. The study was randomised, double-blind, and large, with over 7000 patients from 32 countries.
The investigators found a reduction in exacerbations and need for oral and systemic steroids in the budesonide group and an improvement in asthma control.

The study has strengths and weaknesses. Strengths include the large size, and the pragmatic design means that it is looking at the effectiveness of the intervention and the findings should be generalisable. Weaknesses include the high number of dropouts.

The other interesting outcome is that there was a reduction in growth in children taking budesonide, of 0.43 cm a year. The reduction was similar in young children taking 200 µg daily or older children taking 400 µg daily. Final height is unlikely to be affected with these small doses but it is a timely reminder that doses of budesonide as low as 200 µg daily have measurable systemic effects. Higher doses will inevitably have greater effects and optimising the dose is clearly important and highlighted in the new asthma guidelines.

Anne E Tattersfiled, Tim W Harrison, Lancet; March, 2003; 29 : 1066-67.




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