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CLINICAL REVIEW:
Anita K M Zaidi, Shally Awasthi, and H Janaka deSilva
Burden of infectious diseases in South Asia
BMJ 2004; 328: 811-815 [Full text]
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Rapid Responses published:

[Read Rapid Response] The "Other India" and the statistics that may understate its problems
Subodh B. Joshi   (28 March 2005)
[Read Rapid Response] Risk events and disease causal chains of Acute Infectious Paediatric Diarrhoea
Rajendra P Deolankar   (7 May 2005)

The "Other India" and the statistics that may understate its problems 28 March 2005
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Subodh B. Joshi,
Cardiology Fellow
Royal Melbourne Hospital

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Re: The "Other India" and the statistics that may understate its problems

Dear Sir,

I would like to thank the BMJ for its issue dedicated to the health of South Asia (3rd April 2004). Having spent the first half of 2004 in northern India working as a volunteer doctor, the articles provided valuable data to support the experiences I had. There are an estimated 576,480 child deaths per year from diarrhoea*, 64% of women in India receive no antenatal care^, and, as stated in an earlier BMJ issue, 52% of Indian children have stunted growth.

In some circumstances, statistics seem to understate the magnitude of the problem. As pointed out by Zaidi et al*, laboratory confirmation by culture of diseases such as typhoid is rarely attempted, but clinical typhoid is seen frequently in practice. The burden of HIV in India may also be far greater than 4.58 million persons infected*. The social stigma associated with an HIV positive family member, and the lack of availability or affordability of anti-retroviral therapy, leaves little incentive to get tested for the virus.

The above appalling figures on health contrast starkly with impression we may have of India from abroad. However, this positive image also reflects the truth; the economy is growing rapidly, lead by the IT sector and manufacturing, and work in an increasing number of industries is being outsourced to India. Indeed the burgeoning middle class in India enjoys a lifestyle and standard of healthcare comparable to developed nations. The point often missed is that the vast majority of Indians, 700 million or so, live in rural areas, sometimes in grinding poverty, where even the most basic amenities are still lacking.

As health in developed countries continues to improve and our attention is increasingly turned towards the very worthy, but expensive, treatment of chronic illnesses, the need for young doctors to spend time working in underprivileged regions is greater than ever. The foundations of western medicine are in the treatment of ailments that, sadly, still exist in the developing world, and it is there that the lessons of public health are most effectively taught. Most importantly though, in addition to making a contribution to the health of those less fortunate, doctors, as part of their training, ought to at least learn that this “other” world exists.

Dr Subodh B. Joshi MBBS (Melb), MRCP (Ed), Royal Melbourne Hospital Australia

*BMJ 2004;328:811-815, ^BMJ 2004;328:816-819, BMJ 2000; 321: 809-812

Competing interests: None declared
Risk events and disease causal chains of Acute Infectious Paediatric Diarrhoea 7 May 2005
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Rajendra P Deolankar,
Assistant Director
National Institute of Virology, 20 A Dr. Ambedkar Road, Pune 411 001. INDIA

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Re: Risk events and disease causal chains of Acute Infectious Paediatric Diarrhoea

The disease burden due to Acute Infectious Paediatric Diarrhoea (AIPD) is quite high in developing countries. However, several other diseases exist as backend or front-end events of AIPD. The disease causal chains (DiCC) are rarely studied in infectious diseases. Burden of several infectious diseases rely on certain back events of DiCC. Front-event measures are like pruning the branches of disease tree while back event measures uproot the tree. The DiCC’s should be studied as a spatial epidemiological problem for all the diseases together. The AIPD DiCC’s drawn in this note are just to provide the model.

 Mapping the risk events

(I)                 “Rotavirus (Ro)” triggers “Acute infectious paediatric diarrhoea (Da)”. “Ro” also triggers “Diabetes (Ds) [1]”, an autoimmune disease. “Da” and “Ds” are prevented (denoted by “Da-“ and “Ds-“ respectively) in a child having “sufficient immunity (Is+)”. “Is+” is seen in exclusively breast-fed infants. “Is+” is required to face the “infection (In)” of “Ro” or “Pathogens responsible for diarrhoea other than rotavirus (NRo)”.

(II)              “Marginal immunity (Is+/-)” coupled with “In” cause successful “production of limited enterotoxin (E+/-) [2]” due to growth of pathogen. NSP-4 protein of rotavirus is an enterotoxin “Production of excessive enterotoxin (E)” coupled with “marginal nervous control (NC+/-) on fluid secretion” due to the inadequacy of neurotransmitter enkephalins [3] leads to “Da” and thereafter “Is+”.

(III)             “Immunity is impaired – or immunodeficiency is subjected -- or immunity is lacking (IdIL)” due to “Unhygienic conditions and malnutrition (UM)”. This is common in communities having low socio-economic status. UM promote the chances of several other infections and gut dysbiosis [4] that leads to both “IdIL” and “In”. “E” is the result of combined action of “IdIL” and “In”. “E” coupled with “NC+/-“ leads to diarrhoea. Appropriate intervention leads to complete recovery and health.

(IV)           Enkephalin inadequacy becomes functional only when successful production of “E” due to pathogen replication causes intracellular calcium mobilization. Neurotransmitters Serotonin and Vasoactive Intestinal Peptide are also involved in rotavirus diarrhoea [5]. A child having “Da” due to “E” and “Loss of nervous control (NC-) on fluid secretion” may survive but might have depleted vitamin A [6] and other nutrients that render it malnourished. Such a child is susceptible to other diseases [7] and hence is termed as “vulnerable (VDa) child due to diarrhoea”. A “VDa” child might die due to other diseases causing “Death (DhVDa)” or lead to “IdIL” a vicious cycle.

(V)              “Death (DhR) of a child” could happen due to “Acute infectious (rotavirus) diarrhoea (Da)”

(VI)           Adequacy of enkephalins could lead to “Da-“. but may not stop replication of virus in the intestine. Replication of virus in the absence of adequate barrier may allow the virus to cross the intestinal barrier causing extra-intestinal complication of virus like “Ds”. Autoimmune diabetes due to agents other than rotavirus also occurs.

(VII)         “Ds” could also occur after “Da”

 

List of Risk events

S. No.

Abbreviation

Brief description
  1.  

Da

Acute Infectious Paediatric Diarrhoea
  1.  

Da-

Prevention of diarrhoea
  1.  

DhR

Death of a child attributed to diarrhoea
  1.  

DhVDa

Death of a vulnerable child
  1.  

Ds

Diabetes, an autoimmune disease triggered by Rotavirus
  1.  

Ds-

No diabetes
  1.  

E

Production of excessive enterotoxin
  1.  

E+/-

Production of limited enterotoxin
  1.  

IdIL

Low immunity
  1.  

In

Infection
  1.  

Is+

Sufficient immunity
  1.  

Is+/-

Marginal immunity
  1.  

NC-

Loss of nervous control
  1.  

NC+/-

Marginal nervous control
  1.  

NRo

Pathogens responsible for diarrhoea other than rotavirus
  1.  

Ro

Rotavirus infection
  1.  

UM

Unhygienic conditions and malnutrition.
  1.  

VDa

Vulnerable child due to diarrhoea

 

Disease Causal Chains (DiCC)

 

S. No.

Outcome

Back event-1

Back enent-2

Back event-3

Back event-4

Back event-5

1

Da-, Ds-

Is+

 

 

 

 

 

 

In

 

 

 

 

2a

Is+

Da

Nc+/-

 

 

 

 

 

 

E+/-

Is+/-

 

 

 

 

 

 

In: Ro

 

 

2b

Is+

Da

Nc+/-

 

 

 

 

 

 

E+/-

Is+/-

 

 

 

 

 

 

In: NRo

 

 

3

Da

NC+/-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In

UM

 

 

4a

DhVDa

VDa

Da

NC-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In: Ro

UM

4b

DhVDa

VDa

Da

NC-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In: NRo

UM

5a

DhR

Da

NC-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In: Ro

UM

 

5b

DhR

Da

NC-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In: NRo

UM

 

6

Ds

Da

NC-

 

 

 

 

 

 

E

IdIL

UM

 

 

 

 

 

In: Ro

UM

 

7

Ds

Da-

NC+

 

 

 

 

 

 

IdIL

 

 

 

 

Interpretation:

 

  1. Prevention of unhygienic conditions and malnutrition is the golden rule for developing countries to prevent DiCC 3, 4a, 4b, 5a, 5b and 6. This is a back-end event giving rise to several diseases at front-end; DiCC’s are drawn only for diseases associated with diarrhoea pathogens.
  1. Effect of prevention of dysbiosis through use of prebiotics or probiotics on enteric nervous system is a virgin area of research. Whether nervous controls depend upon the health of eco-organ (native gut microbiota) is yet to be investigated. Use of probiotics [8] for treatment and lactic fermented foods [9] for prevention of acute infectious paediatric diarrhoea is known.
  1. Effect of exposure to the morning Sun thereby up-regulating the nervous controls is the virgin area of research. Sufficiency of vitamin D [10] is expected to reduce intracellular calcium mobilization thereby diarrhoea. Winter is a confounder of rotavirus diarrhoea. Vitamin D deficiency is common during winter.
  1. Human milk contains the following:

Antibodies- binds to rotavirus; action similar to vaccine [11] but passive

Bifidobacteria Growth Factor (Prebiotics)- At the back of beneficial action of bifidobacteria [12]

Bifidobacteria- Cytokine modulator, prevents inflammation thereby progression from “E” to “Da and onwards” [13].

Rotavirus disease is not characterized by inflammation. How inflammatory conditions within the mucosa affect rotavirus diarrhoea remain largely unanswered [14].

Bifidobacteria enhance immune-mediated protection [15] thereby down regulation of IdIL in DiCC 3, 4a, 4b, 5a, 5b and 6.

Trypsin Inhibitor (Inhibits trypsin. Trypsin enhances rotavirus infectivity [16]; therefore trypsin inhibitor down regulates “E” in DiCC 3, 4a, 4b, 5a, 5b and 6) [17]

Lactadherin (inhibits rotavirus binding, down regulates “E” in DiCC 3, 4a, 4b, 5a, 5b and 6) [18]

Lactoferrin (hindering adsorption and internalisation into cells through specific binding to cell receptors and/or viral particles; down regulates “E” in DiCC 3, 4a, 4b, 5a, 5b and 6) [19]

Other milk proteins [20]

Vitamin A, D, Minerals etc and

Other factors [21] and will prevent multiple events.

DiCC also points out that role of human milk in nervous control of fluid secretion is a virgin area for research.

  1. Effect similar to human milk may be expected from designers food or value added functional foods like hyperimmune animal colostrums or milks. How rotavirus vaccination of mothers or dairy animals affects immune components of milk other than antibodies is a virgin area for research. Several value added products could be developed from dairy milks.
  1. Speaking of rotavirus vaccine [22], it will not only prevent progression from “IdIL” to “E” in DiCC 5a but will also prevent the same in DiCC 4a. It means rotavirus vaccine can prevent not only deaths due to rotavirus diarrhoea but also reduce to some extent deaths from measles or respiratory viruses. However, it is contemporary understanding that rotavirus vaccine will not prevent diarrhoea triggered by pathogens other than rotaviruses as shown in DiCC 4b and 5b. Vaccine is expected to prevent “E” in DiCC 6, however, safety test of vaccine are required as live vaccine virus itself may trigger DiCC 6. Toxoid vaccine might stop “Da” but may trigger DiCC 6. Viraemia is common in children infected with rotavirus, which may be associated with extra-intestinal involvement [23].
  1. Oral rehydration therapy [24] will prevent progression from “Da” to “DhR” in DiCC 5a and 5b but will not prevent progression from “Da” to “VDa” in DiCC 4a and 4b. It will also not prevent progression of “Da” to “Ds” in DiCC 6.
  1. The Racecadotril [25] will prevent progression from “NC-“ to “Da” in DiCC 5a, 5b and 6 but will not prevent progression from “Da” to “Ds” in DiCC 6.

References

1.      Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD, Colman PG, Harrison LC. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. 2000 Aug;49(8):1319-24.[Full Text]

2.      Ball JM, Mitchell DM, Gibbons TF, Parr RD. Rotavirus NSP4: a multifunctional viral enterotoxin. Viral Immunol. 2005;18(1):27-40. [Medline]

3.      Farthing MJ. Novel agents for the control of secretory diarrhoea. Expert Opin Investig Drugs. 2004 Jul;13(7):777-85.[Medline]

4.      Deolankar RP. Weaning/Post-weaning dysbiosis: standardization of assay of dysbiosis is required. Gut Online.21 April 2004. [Full Text]

5.      Kordasti S, Sjovall H, Lundgren O, Svensson L. Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea. Gut. 2004 Jul;53(7):952-7.[Full Text]

6.      Alvarez JO, Salazar-Lindo E, Kohatsu J, Miranda P, Stephensen CB. Urinary excretion of retinol in children with acute diarrhea. Am J Clin Nutr. 1995 Jun;61(6):1273-6.[Medline]

7.      Jason J, Archibald LK, Nwanyanwu OC, Sowell AL, Buchanan I, Larned J, Bell M, Kazembe PN, Dobbie H, Jarvis WR. Vitamin A levels and immunity in humans. Clin Diagn Lab Immunol. 2002 May;9(3):616-21.[Full Text]

8.      Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr. 2001 Oct;33 Suppl 2:S17-25.[Medline]

9.      Lorri W and Svanberg U. Lower prevalence of diarrhoea in young children fed lactic acid-fermented cereal gruels. Food Nutr Bull, 1994; 15: 57-63.[Full Text]

10.  Deolankar RP. Vitamin D deficiency may be mediating rotavirus diarrhoea. bmj.com, 13 Mar 2004.[Full Text]

11.  Van de Perre P. Transfer of antibody via mother's milk. Vaccine. 2003 Jul 28;21(24):3374-6.[Medline]

12.  Petschow BW, Talbott RD. Growth promotion of Bifidobacterium species by whey and casein fractions from human and bovine milk. J Clin Microbiol. 1990 Feb;28(2):287-92.[Full Text]

13.  Lammers KM, Brigidi P, Vitali B, et al. Immunomodulatory effects of probiotic bacteria DNA: IL-1 and IL-10 response in human peripheral blood mononuclear cells. FEMS Immunol Med Microbiol 2003;38:165–72 [Medline]

14.  Morris AP, Estes MK. Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VIII. Pathological consequences of rotavirus infection and its enterotoxin. Am J Physiol Gastrointest Liver Physiol. 2001 Aug;281(2):G303-10.[Full Text]

15.  Shu Q, Qu F, Gill HS. Probiotic treatment using Bifidobacterium lactis HN019 reduces weanling diarrhea associated with rotavirus and Escherichia coli infection in a piglet model. J Pediatr Gastroenterol Nutr. 2001 Aug;33(2):171-7.[Medline]

Saavedra J. Probiotics and infectious diarrhea. Am J Gastroenterol. 2000 Jan;95(1 Suppl):S16-8.[Medline]

16.  Estes MK, Graham DY, Mason BB. Proteolytic enhancement of rotavirus infectivity: molecular mechanisms. J Virol. 1981 Sep;39(3):879-88. [Full Text]

17.  Chowanadisai W, Lonnerdal B. Alpha(1)-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability. Am J Clin Nutr. 2002 Oct;76(4):828-33.[Full Text]

Jayashree S, Bhan MK, Kumar R, Bhandari N, Sazawal S. Protection against neonatal rotavirus infection by breast milk antibodies and trypsin inhibitors. J Med Virol. 1988 Nov;26(3):333-8.[Medline]

18.  Newburg DS, Peterson JA, Ruiz-Palacios GM, Matson DO, Morrow AL, Shults J, Guerrero ML, Chaturvedi P, Newburg SO, Scallan CD, Taylor MR, Ceriani RL, Pickering LK. Role of human-milk lactadherin in protection against symptomatic rotavirus infection. Lancet. 1998 Apr 18;351(9110):1160-4.[Medline]

19.  Seganti L, Di Biase AM, Marchetti M, Pietrantoni A, Tinari A, Superti F. Antiviral activity of lactoferrin towards naked viruses. Biometals. 2004 Jun;17(3):295-9.[Medline]

20.  Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr. 2003 Jun;77(6):1537S-1543S.[Medline]

21.  J.T.May (1997) Clinical significance and recent studies of the anti-infective properties and infectious contaminants in breast milk. In "Breastfeeding, the natural advantage" NMAA International conference, Sydney p138-144.

J.T. May (1995). Human milk antimicrobial and microbial contaminants relevant to human milk. In Breast milk and special care nurseries, problems and opportunities, Aust Lactation Consultants Association Press,19-23.[Link]

22.  Braine T. Rotavirus vaccine introduction in Mexico sets precedent. Bull World Health Organ. 2005 Mar;83(3):167. Epub 2005 Mar 16.[Full Text]

23.  Chiappini E, Azzari C, Moriondo M, Galli L, de Martino M. Viraemia is a common finding in immunocompetent children with rotavirus infection. J Med Virol. 2005 Jun;76(2):265-7.[Medline]

24.  Rao MC. Oral rehydration therapy: new explanations for an old remedy. Annu Rev Physiol. 2004;66:385-417.[Medline]

25.  Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med. 2000 Aug 17;343(7):463-7.[Full Text]

 

Competing interests: None declared