Cermin Dunia Kedokteran

Various Types of Specific Acquired

Deficient Immune Status (SADIS) following

Various Kinds of Microbial Infection -

5a. the clinical management of diseases

that may produce SADIS with lymphocyte

predominance

R.A. Handojo*, Anggraeni Inggrid Handojo**

* The Indonesian Association of Pulmonologists, Malang, Indonesia

** The TB Center of Surabaya, Indonesia

Diseases that may produce SADIS may have lymphocyte

predominance or lymphocyte depletion. There are three catego-

ries of diseases that in the advanced stage may produce SADIS

(fig. 1), i.e.:

Fig. 1. Three categories of specific acquired deficient immune status

(SADIS)

Category I

Category 2

Category 3

the Tb-type of SADIS

brought about by:

Bacteria

: M.

tuberculosis

: H. pylori

DNA-viruses

HBV,

lPV, HSV-2, EBV

RNA-virus

HCV.

the Lk-type of SADIS

brought about by:

DNA-virus

EBV

RNA-viruses

HTLV-I,

HTLV-II.

the Lp-type of SADIS

brought about by:

RNA-viruses

: HTLV-III

(HIV-1),

HIV-2

bacterium

: M.

leprae.

Diseases that may progress to the tuberculosis-type (Tb-

type) of SADIS, comprising diseases caused by the tubercle

bacillus, the Helicobacter pylori, the hepatitis B virus (HBV), the

hepatitis C virus (HCV), the human papilloma virus (HPV), the

herpes simplex virus type 2 (HSV-2) and the Epstein Barr virus

(EBV).

Diseases that may produce the leukemia-type (Lk-type) of

SADIS, comprising a disease caused by the EBV, and diseases

caused by the human T-cell lymphotrope virus type I (HTLV-I)

and the human T-cell lymphotrope virus type II (HTLV-II).

Diseases that may progress to the leprosy-type (Lp-type) of

SADIS, comprising diseases caused by the human immunodefi-

ciency virus type I (HIV-1), the human immunodeficiency virus

type II (HIV-2) and a disease caused by the leprosy bacillus.

The Tb-type of SADIS has primary solid malignancy as

disease expression that is located in an organ of the host, e.g. the

lung (bronchogenic carcinoma), the nasopharynx (nasopharynx

carcinoma), the liver (primary hepatocellular carcinoma) and the

cervix of the uterus (cervix carcinoma). The existence of T-

lymphocyte predominance is a characteristic of the Tb-type of

SADIS. In addition, there is a predominance of the cellular

immune system in comparison to the humoral immune system

(fig. 2).

Fig. 2. Some characteristics of the three types of SADIS

Type of

SADIS

Disease

expression

Lymphocytes

CMIS*

HIS**

Tb-type primary

malignancy

(epithelial carcinoma)

predominance >

Lk-type primary

malignancy

(leukemia, NHL,***

Hodgkin's dis.)

predominance >

Lp-type

· AIDS, opportunistic

malignancy

depletion <

· KK-type leprosy

depletion

< 1

Note:

CMIS : cell mediated immune system

HIS : humoral immune system

NHL : non-Hodgkin

s lymphoma

The Lk-type of SADIS has primary hematologic malignancy

as disease expression that is located in tissues of organs of the

host, e.g. in lymph nodes (malignant lymphoma) and in bone

marrow (leukemia). Lymphocyte predominance which is based

on neoplastic proliferation of lymphocytes, is a characteristic of

the Lk-type of SADIS. There is also predominance of the cellular

immune system when compared to the humoral immune system

(fig. 2).

The Lp-type of SADIS that is brought about by HIV-1 has

the acquired immunodeficiency syndrome (AIDS) as disease

manifestation. It is characterized by the emergence of opportu-

nistic infections and the development of opportunistic malignan-

cies as well. The Lp-type of SADIS which is caused by the

leprosy bacillus has the lepromatous leprosy (LL-leprosy) as

disease manifestation which is characterized by the existence of

primary clinical resistance to antileprosy chemotherapy. It has

neither primary nor opportunistic malignancy as disease expres-

sion. In addition, it is characterized by the absence of opportu-

nistic infection. There is lymphocyte depletion in both diseases.

Predominance of the humoral immune system in comparison to

the cell mediated immune system is found in the Lp-type of

SADIS (fig. 2).

The specific immune spectrum and the specific immuno-

logic characteristics of a disease that in its Advanced stage may

produce SADIS, constitute the specific immunologic fingerprint

of the disease. Determination of the immunologic fingerprint of

diseases following infection with the causative pathogens that

can bring about the development of SADIS, may provide rational

basis for the proper tackling and solving of problems that may

arise in the fight against the causative organisms. Knowledge of

immunologic fingerprints not only enables the diagnosis of the

related disease to be made more accurately but also provides a

more rational basis for effective clinical management to be based

on.

Diseases of the same category of SADIS may have identical

or almost identical principles of clinical management. In addi-

tion, knowledge of immunologic fingerprint has substantially

broadened our knowledge and understanding of the pathways

through which the disease may progress or regress. Achievement

of a defined knowledge of clinical management of diseases that

have undergone long-term and thorough tackling and solving of

the related problems, such as tuberculosis and leprosy, may serve

as rational paradigm for effective clinical management to be set

up in aid of other diseases that may produce the same category of

SADIS.

I) THE CLINICAL MANAGEMENT OF DISEASES

THAT MAY PRODUCE THE TB-TYPE OF SADIS

Based on the characteristics of the immunologic fingerprint,

the principles of the clinical management of diseases that may

produce the Tb-type of SADIS are divided into the following:

A) The clinical management of diseases that emerge as disease

expression of the acute (L-type) and the chronic type (K-type)

immune status (fig. 3).

The institution of "the early kill" of causative microbial

pathogens through the advent of specific anti-microbial chemo-

therapy when disease expression is of the L-type or K-type

immune status.

The enhancement of the "early kill" of microbial pathogens

through the concomitant use of immunomodulators during the

early phase of anti-microbial chemotherapy when disease

expression is of the K-type immune status at start of chemo-

therapy.

The institution of immunotherapy with BCG following

cessation of a successful anti-microbial chemotherapy for the

Fig. 3. The clinical management of diseases that may bring about develop-

ment

Tb-type

SADIS

Purpose: Back to basic which means back to the L-type immune status

Prevailing Immune Status

L-type K-type

KK-type

(Tb-type SADIS)

· early kill of microbial · early kill of microbial · early kill of microbial

pathogen thru specific pathogen thru specific pathogen thru:

antimicrobial chemo- antimicrobial chemo- · surgery

therapy

· augmentation of early

kill of microbial

pathogen thru

immunomodulator

· stabilization of cure

thru immunotherapy

with BCG

· chemotherapy

· radiotherapy

· stabilization of cure

thru specific anti-

microbial chemo-

therapy (when avail-

able)

· stabilization of cure

thru immunotherapy

with BCG.

stabilization of the cure when disease expression is of the K-type

immune status at start of chemotherapy.

B) The clinical management of diseases that emerge as disease

expression of the KK-type immune status (Tb-type of SADIS)

(fig. 3).

The institution of the "early kill" of microbial antigen

through the advent of:

1.1. surgical resection of the lesion.

1.2. cytotoxic chemotherapy.

1.3. radiotherapy,

for the regression of immune status from the KK-type to the K-

type or even further to the L-type immune status.

The enhancement of the "early kill" of microbial pathogen

through the use of specific anti-microbial chemotherapy for the

stabilization of the cure following achievement of complete

remission of the lesion.

The inoculation of BCG as immuno-therapy for the stabili-

zation of the cure following the achievement of complete re-

mission of the lesion when specific anti-microbial chemotherapy

is not available.

A1) The institution of the "early kill" of microbial antigen

through the advent of specific anti-microbial chemotherapy.

The tubercle bacillus is the prototype of microbial pathogens

that can bring about the Tb-type of SADIS. The advent of

adequate anti-TB chemotherapy is crucial in the fight against the

tubercle bacilli before the disease may progress to disease mani-

festation of the Tb-type of SADIS.

Anti-TB chemotherapy has anti-microbial activity and has

the added advantage of being able to induce regression of

immune status from the K-type to the L-type aiming at the

achievement of better protective immunity. The "early kill" of

tubercle bacilli through the use of adequate anti-microbial

chemotherapy is essential for the achievement of a successful

result at end of treatment. Anti-tuberculosis drugs exert bacteri-

cidal activity only during a treatment period of six months

(1)

During this period, killing of tubercle bacilli and regression of

immune status take place. Prolongation of chemotherapy using

the same treatment regimen produce enhancement of protective

capacity without further anti-microbial activity of the drugs

(1)

Enhancement of protective immunity is based on the augmenta-

tion of bactericidal activity of the macrophage through further

regression of immune status to the L-type.

The advent of anti-Helicobacterpylori drugs such as tetracy-

cline hydrochloride or amoxicillin, metronidazole and colloidal

bismuth subcitrate, known as the triple therapy, has been shown

to be effective for the institution of the "early kill" of Heloco-

bacter pylori when disease expression is of the L-type or K-type

immune status. A treatment regimen consisting of colloidal

bismuth subcitrate, tetracylin hydrochloride and metronidazole

has been shown to eradicate Helicobacter pylori infection in 91%

of an Australian dyspeptic population (quoted from : Asian

Medical News; Medical Tribune International vol. 12, October 2,

1990).

Current anti-ulcer regimen using drugs usually termed the

receptor antagonists, now designated as immunomodulators,

have been successful but the ulcer recurrence is an inconvenient

and sometimes a serious problem

(2)

. Almost 80% of duodenal

ulcer patients caused by Helicobacter pylori that healed follow-

ing the advent of H

-receptor antagonists for the duration of

46 weeks, developed relapse within one year, but if an anti-

microbial regimen consisting of colloidal bismuth subcitrate,

metronidazole plus amoxicillin or tetracycline hydrochloride

(triple therapy) is used as well to control Helicobacterpylori, the

relapse rate is reduced to less than 10% if it is completely

eradicated

(3,4,5)

Two weeks treatment using triple therapy is

adequate to achieve eradication of Helicobacter pylori in most

patients

(2)

The result of treatment using interferon and aciclovir in

patients suffering from chronic hepatitis B, revealed that both

drugs are effective for the institution of the "early kill" of HBV,

when disease expression is of the K-type immune status. The

result of anti-viral treatment in 12 patients suffering from chronic

hepatitis B conducted in 1985 revealed that combination therapy

of interferon and aciclovir appeared to be obviously more effec-

tive than when interferon or aciclovir was given as mono-

therapy

(6)

. Alpha-interferon has a favourable effect on viral

replication and on the levels of liver enzymes in 2550% of

selected patients with chronic hepatitis B virus infection

(7,8)

Active viral replication of HBV is characterized by the persistent

presence of HBs-Ag, HBe-Ag and HBV-DNA-polymerase in

blood.

The presence of HBs-Ag only indicates the emergence of

virus-latency; anti-HBe-antibody may also be encountered. During

the latent phase of virus elimination, HBs-Ag is no longer

detectable in blood; anti-HBs-antibody and anti-HBe-antibody

may be encountered . Anti-viral treatment in chronic hepatitis

(9)

patients is exclusively meaningful when active viral replication

exists which can be confirmed by a positive result of HBs-Ag and

HBe-Ag test

(9)

. Combination of interferon plus aciclovir may

induce a state of virus-latency in 80% of chronic HBe-Ag

positive patients

(6)

; some may even be cuffed

(10)

. The accelerated

seroconversion of HBe-Ag coincides with the improvement of

clinical, biochemical and histological parameters

(10)

Based on the result of a study on the efficacy of interferon

given to 18 patients suffering from clinically apparent cirrhosis

of the liver related to chronic hepatitis B, Hoofnagle et al.

(11)

pointed out that it is quite reasonable to treat patients with

cirrhosis of the liver due to chronic hepatitis B with alpha-

interferon. During treatment for the duration of average 12

weeks, HBe-Ag and hepatitis B-virus-DNA disappeared from

blood in 12 patients. One to 14 months following cessation of

treatment, hepatitis B-virus-DNA was encountered again in 6 of

them. The other 6 patients in whom hepatitis B-virus-DNA was

no longer found, remission was achieved in all of them. During

a follow-up period of 4.2 years, no signs of cirrhosis were

encountered

(11)

At present, there are no uniformly effective drugs against

infection with HCV, an RNA-virus. Clinical drug trials have

shown that treatment using recombinant interferon-alpha for six

months can normalize liver function in up to 46% of patients.

However, the relapse rate following cessation of successful

therapy is high (up to 51%)

(12)

Treatment with interferon-alpha has a favourable effect on

serum liver enzyme activities and on the histologic abnormalities

in approximately 50% of patients with chronic hepatitis C

(13,14)

There is correlation of the response to treatment and the decrease

of the number of hepatitis C-RNA in serum

(15)

. Alpha-interferon

and beta-interferon, derived respectively from leukocyte and

from fibroblast, are produced in the body of the host as natural

response to viral infection. They have a very broad spectrum of

anti-viral activity

(16)

. Gamma-interferon is produced by T-lym-

phocyte following antigen specific and non-specific activation

and is a lymphokine or cytokine with immunomodulating capa-

city

(17)

Anti-viral chemotherapy must have the capacity to stop

replication of virus, termed the virustatic action, in infected cells

without bringing about the development of radical alteration in

the normal metabolism of cell. A virologic aspect that deserves

attention is that available drugs are in general effective against

viruses which are replicating and not effective against viruses

which are not replicating in the cell of the host, the latter being

encountered in latent herpes virus infection

(16)

An initial episode of herpes genitalis is a good indication for

anti-microbial treatment with aciclovir

(16)

. Aciclovir has a selec-

tive virustatic action. This action is based on the inhibition of the

viral DNA-polymerase which is essential for the replication of

the viral DNA. The herpes simplex virus type 1 (HSV-1) and the

herpes simplex virus type 2 (HSV-2) are sensitive and the

varicella zoster virus (VZV) is moderately sensitive to aciclovir

in vitro

(10)

. There is some activity of aciclovir against the EBV

(16)

The cytomegalovirus (CMV) is insensitive to aciclovir

(10,16)

Aciclovir is not effective against latent herpes virus infec-

tion

(10,16)

and has only a marginal therapeutic effect on recurrent

herpes infection of the skin and mucoid membrane, provided it is

employed in the early phase of the disease

(10)

. The most striking

characteristic of herpes viruses is that they persist in the body of

the host following infection

(10)

. Aciclovir shortens the duration of

viral shedding, the time for the achievement of cure, the duration

of symptoms, and inhibits the development of new lesions during

treatment of patients suffering from herpes genitalis

(16)

Treatment using aciclovir doesn't have influence on the rate

of development and the severity of herpes genitalis relapses.

Foscarnet (phosphonoformate) inhibits the DNA-polymerase of

herpes virus

(18)

. It is mainly used in immunocompromised pa-

tients with resistent HSV and VZV infections to aciclovir and

with resistent CMV infection to ganciclovir

(16)

. An synergistic

anti-CMV-effect in vitro of ganciclovir and foscarnet has been

reported

(19,20)

. Casuistic reports and observations revealed

encouraging results of treatment with the above combination

(21,22)

A2)

The enhancement of the early kill of microbial pathogen

through the advent of immuno-modulators.

The "early kill" of microbial pathogens through the use of

adequate anti-microbial chemotherapy can be augmented by the

use of immuno-modulators, such as cimetidine, isoprinosine and

levamisole. The advent of cimetidine concomitantly during the

early phase of anti-TB chemotherapy accelerate the incidence of

sputum negativity

(23)

. Immuno-modulators enhance the micro-

bicidal activity of the macrophage. When given in the absence of

anti-microbial chemotherapy, immuno-modulators may delay

the progression of immune status from the K-type to the KK-type

(SADIS). It is intriguing to speculate that immuno-modulators

have the capacity of an immuno-biological response modifier.

They likely have the capacity to modify immune status from the

prevailing one to a previous one from which it has progressed or

regressed. Immuno-modulator as a therapeutic adjunct in the

administration of anti-microbial chemotherapy has to be given

during the early phase of chemotherapy or even preceding the

commencement of chemotherapy. When given following

cessation of a successful anti-microbial chemotherapy, immuno-

modulator may have a deleterious effect on the outcome of

chemotherapy; it may accelerate the development of relapse

following cessation of successful chemotherapy.

It can be expected that the concomitant use of immuno-

modulator and specific anti-microbial chemotherapy in patients

suffering from diseases that can produce the Tb-type of SADIS

in their chronic stage (K-type immune status), may accelerate the

regression of immune status from the K-type to the L-type. This

implies that in patients with gastric ulceration due toHelicobacter

pylori infection, healing of ulcer will be accelerated.

The use of immuno-modulator in patients with chronic

hepatitis can be expected to delay the progression of chronic

hepatitis to the development of malignancy.

A3)

The stabilization of cure through the advent of immuno-

therapy.

Inoculation of BCG for the purpose of immunotherapy

following cessation of a successful anti-tuberculosis chemo-

therapy in patients with chronic tuberculosis, gives rise to further

regression of immune status from the K-type to the L-type,

resulting in the generation of better protective immunity for

better stabilization of the cure achieved at end of chemotherape

(24)

Inoculation of BCG as immunotherapy has to be carried out

following cessation of a successful anti-TB chemotherapy. When

given preceding the commencement of chemotherapy, inocula-

tion of BCG may have a deleterious effect on the prevailing

immune status as was evidenced by the development of a down-

grading reaction in the immune spectrum of tuberculosis, result-

ing in a further deterioration of protective immunity

(25)

. When

given during the implement of anti-TB chemotherapy, BCG will

be killed by the anti-microbial activity of the anti-TB drugs.

The result of specific immunotherapy with BCG for the

enhancement of protective immunity achieved at end of a

successful anti-TB chemotherapy, opens new prospects for the

investigation whether inoculation of BCG as non-specific

immunotherapy can enhance protective immunity achieved at

end of a successful anti-microbial chemotherapy in patients with

chronic disease due to for instance theHelicobacterpylori or the

hepatitis B virus infection.

B1) The institution of the "early kill" of microbial pathogen

through the mechanism of regression of the KK-type immune

status.

The existence of an optimally functioning immune defense

system is a conditio sine qua non for the proper functioning of

anti-microbial activity of anti-tuberculosis drugs.

Progression of the K-type immune status which has chronic

TB as disease expression to the KK-type immune status which

has primary localized malignancy as disease manifestation, is

characterized by the existence of a defective immune defense

system especially related to cell mediated immunity.

Anti-TB chemotherapy is no longer effective when employ-

ed to tuberculosis patients during the advanced stage of the

disease that have primary malignancy as disease expression.

(unpublished data). It is like doing shadow boxing; much energy

is spent without ever hitting the opponent.

Based on its localized character, clinical management of

primary malignancy as disease manifestation of the TB-type of

SADIS, whatsoever is the causative pathogen, should aim at the

achievement of rapid complete remission of the lesion, i.e.

through the implement of surgical resection of the malignancy as

far as it is still operable, curable and resectable. The principal

advantage of surgery over radiotherapy or cytotoxic chemo-

therapy lies in the absence of the development of seccundary

malignancy. Lymphocyte predominance is a characteristic of the

Tb-type of SADIS. Clinical management of primary malignancy

as disease expression of the TB-type of SADIS, no matter what

the causative organism may be, should aim at the achievement of

a complete remission of the malignancy through normalization

of the prevailing lymphocyte predominance by way of the advent

of immuno-suppressive medication especially when the disease

is no longer resectable or operable. Immuno-suppression through

the advent of radiotherapy and/or the use of cytotoxic chemo-

therapy are eligible tools for the normalization of the lymphocyte

predominance.

Radiotherapy remains a localized form of treatment for what

is usually a disease that tends to disseminate. Its principal

advantage over surgery is the preservation of structure and

function of treated organs

(26)

. It is unlikely that a malignancy with

a mass greater than 5 cm in diameter can be sterilized by radio-

therapy

(27)

. Radiation induces profound lymphopenia in lym-

phoid organs and in the general circulation as well. In addition,

it suppresses most immuno-competent cell function

(28)

. X-ray

irradiation has a toxic effect on proliferating and intermitotic

cells as well and has the effect of cycle-nonspecific drugs in

addition. The great majority of immunologically competent

lymphocytes are in the intermitotic phase of the proliferaring

cycle. Consequently, radiotherapy may reduce the number of

blood or tissue lymphocytes and may cause a generalized deple-

tion of immunologically competent cells

(28)

Cytotoxic chemotherapy is not selectively toxic for compe-

tent lymphocytes but is potentially capable of killing any cell that

has the capacity to replicate

(28)

. Based on their capacity to kill

cells in different phases of the mitotic cycle, cytotoxic drugs can

act as phase-nonspecific drugs, cycle-specific drugs and cycle-

nonspecific drugs. As cycle-nonspecific drugs, cytotoxic drugs

are equally toxic to both proliferating and intermitotic cells

(28)

Consequently, reduction of the number of lymphocytes or even

lymphocyte depletion may be the outcome of therapy as a great

deal of the immuno-competent lymphocytes are in an inter-

mitotic phase of the proliferating cycle. In general, cytotoxic

chemotherapy and radiotherapy are given separately and in

sequence

(29)

Corticosteroids are important adjuncts to the advent of

immuno-suppressive therapy using cytotoxic chemotherapy

and/or radiotherapy. The production of cytotoxic T-lymphocytes

from the non-cytotoxic precursor cells is diminished by cortico-

steroids in vitro and in vivo as well

. Corticosteroids appear to

stop the T-helper cells from secreting T-cell growth factor by an

indirect effect. They actively preclude macrophages from secret-

ing interleukin-1 which is known to interact with the T-helper

cells that subsequently elaborate T-cell growth factor

(30)

. Con-

sequently, based on their effect on cell mediated immunity,

corticosteroids reduce the number of lymphocytes. The effect of

corticosteroids on humoral immunity is less profound. Chronic

administration of the drug decreases IgG synthesis, while short-

course treatment doesn't dampen primary or secondary antibody

responses

(30)

The achievement of complete response to radiotherapy

and/or cytotoxic chemotherapy as is based on the acievement of

complete remission of the disease is a good prognostic sign.

Achievement of complete remission of pathologic lesion follow-

ing surgical resection or following immuno-suppressive medica-

tion through the advent of radiotherapy and/or cytotoxic chemo-

therapy means the achievement of cure which implies the achieve-

ment of immune status inherent in healthy naturally infected

individuals or in healthy BCG-vaccinated individuals in the

immune spectrum of tuberculosis.

B2) The enhancement of the early kill of microbial pathogen

through the use of anti-microbial chemotherapy.

The institution of specific anti-microbial chemotherapy when

available following the achievement of complete remission of

malignancy through the advent of surgery, cytotoxic chemo-

therapy and/or radiotherapy, is essential for the stabilization of

cure, the mechanism of which is based on the eradication of the

remaining causative microbial pathogens.

Beside its killing effect on the remaining causative microbial

pathogens, anti-microbial chemotherapy has the added advan-

tage of being able to bring about a further shift of the position of

immune status in the immune spectrum of the disease from that

of healthy subjects following natural infection to that of subjects

following vaccination.

B3) Stabilization of the cure following complete remission of

malignant lesion through the advent of immuno-therapy.

When specific anti-microbial chemotherapy is not available

or when the causative pathogen is not known, inoculation of BCG

as immuno-therapy is the eligible alternative measure for the

stabilization of cure. Immuno-therapy through the advent of

BCG is aimed at bringing about further shift of the immune status

that has taken place from the KK-type to the K-type following

complete remission of malignant lesions through the advent of

surgery, radiotherapy or cytotoxic chemotherapy. In other words,

immuno-therapy with BCG following complete remission of

malignant lesions through the advent of surgery, radiotherapy

and/or cytotoxic chemotherapy, may bring about a further shift of

the position of immune status in the immune spectrum of the

disease from that of healthy individuals following natural infec-

tion to that of healthy individuals following vaccination.

In cancer therapy, immuno-therapy is usually employed

after chemotherapy and radiotherapy. Non-specific systemic

immuno-stimulation can be carried out using agents such as

BCG, with the aim of general stimulation of immunologic

responsiveness.

Bacillus Calmette Guerin (BCG) is a viable attenuated strain

of M. bovis obtained by progressive reduction of virulence via

culture medium enriched with beef bile). It is a whole bacillus

vaccine. Bacillus Calmette Guerin acts mainly by stimulating the

reticulo-endothelial system, i.e. the activation of T-cell and

lymphokine production and the activation of macrophage. It also

stimulates natural killer cells which can kill different malignant

cells non-specifically and without previous sensitization

(31)

. It is

possible that macrophages activated by BCG are more active

killer cells and are more efficient in cleaning antigens or antigen-

antibody complexes, or are capable of inducing active participa-

tion of other cells of the immune system in the fight against

proliferating tumor cells

(31)

. Bacillus Calmette Guerin appears to

enhance the production of stem cells, as was measured by

hematopoietic colony formation. In addition, some investigators

have made the suggestion that BCG cross-reacts immunologi-

cally with hepatoma, melanoma and leukemic cells. Immuno-

therapy with BCG is employed as adjuvant treatment following

cytoreductive treatment of measurable cancer in order to destroy

micrometastasis and the residual tumor cells

(31)

II. THE CLINICAL MANAGEMENT OF DISEASES

THAT MAY PRODUCE THE LK-TYPE OF SADIS.

(FIG. 4).

Fig. 4. The clinical management of diseases that may bring about develop-

ment

Lk-type

SADIS

Purpose: Back to basic which means back to L-type immune status

Prevailing Immune Status

L-type K-type

KK-type

(Lk-type SADIS)

· Early kill of microbial

pathogen thru specific

antimicrobial chemo-

therapy

· Early kill of microbial

pathogen thru specific

antimicrobial chemo-

therapy

· Augmentation of early

kill of microbial

pathogen thru

immunomodulator

· Stabilization of cure

thru immunotherapy

with BCG.

· Early kill of microbial .

pathogen thru:

· chemotherapy

· radiotherapy

· Stabilization of cure

thru specific anti-

microbial chemo-

therapy (when avail-

able)

· Stabilization of cure

thru immunotherapy

with BCG.

Like in patients with the Tb-type of SADIS, there is T-

lymphocyte predominance in patients with the Lk-type of SADIS.

There is also predominance of the cellular immune system when

compared to the humoral immune system (fig. 2).

Based on the characteristics of the immunologic fingerprint

and its resemblance to the Tb-type of SADIS, the principles of

clinical management of diseases that may produce the Lk-type of

SADIS are the following:

A) The clinical management of diseases that emerge as disease

manifestation of the acute (L-type) and chronic (K-type) immune

status.

The institution of the "early kill" of causative microbial

pathogens through the advent of specific anti-microbial chemo-

therapy when disease expresion is of the L-type or the K-type

immune status.

The augmentation of the "early kill" of causative microbial

pathogens through the advent of immuno-modulators during

the early phase of anti-microbial chemotherapy when disease

expression is of the K-type immune status at start of chemo-

therapy.

The institution of immuno-therapy following cessation of a

successful anti-microbial chemotherapy for the stabilization of

the cure when disease expression is of the K-type immune status

at start of chemotherapy.

B) The clinical management of diseases that emerge as disease

expression of the KK-type immune status (Lk-type of SADIS).

1) The institution of the "early kill" of causative microbial

pathogens through the advent of:

1.1. cytotoxic chemotherapy

1.2. radiotherapy

for the regression of immune status from the KK-type to the K-

type or even further to the L-type immune status.

2) The enhancement of the

early kill" of causative microbial

pathogens through the use of specific anti-microbial chemo-

therapy for the stabilization of the cure following achievement of

complete remission of the disease.

3) The inoculation of BCG as immuno-therapy for the stabili-

zation of the cure following achievement of complete remission

of the disease when specific anti-microbial chemotherapy is not

(yet) available.

A. The clinical management of diseases that emerge as

disease manifestation of the acute (L-type) and the chronic

(K-type) immune status (fig. 4).

Achievement of cure following EBV-infection occurs spon-

taneously in general in the course of 46 weeks. In some of the

patients symptomsa may persist during months or years; these

patients are considered as suffering from chronic persistent

EBV-infection. Most striking is the presence of antibodies against

EBV-early antigen (EBV-EA) ofteen in high titers

(32)

. There is

hitherto still no effective drug available for the "early kill" of

EBV during the acute and the chronic stage of the disease.

According to Lange and Van der Noorda

, aciclovir has some

activity against EBV.

Of the herpes viruses, the herpes simplex virus type 1 (HSV-

1) and the herpes simplex virus type 2 (HSV-2) are sensitive to

concentrations of aciclovir; the Epstein Barr virus and the cyto-

megalovirus (CMV) are not sensitive to aciclovir. The Varicella-

Zoster-virus (VZV) is moderately sensitive to aciclovir

(11)

Aciclovir is a selective virustaticum. The drug is active following

conversion into aciclovir-triphosphate which takes place in the

cell that is infected with the virus. Aciclovir is much easier bound

to viral thymidine-kinase than to thymidine-kinase of the host.

The action of aciclovir-triphosphate is based on inhibition of the

viral DNA-polymerase which is essential for the viral DNA

replication. It is important to note that aciclovir is not effective in

latent viral infection

(10)

No effective drugs are hitherto available for the "early kill"

of HTLV-I and HTLV-H during the acute and chronic stage of the

disease. In a small group of Japanese patients suffering from

HTLV-I infection in the chronic stage of the disease (tropical

spastic paraparesis), improvement has been observed following

treatment with corticosteroids

(32)

. In other group of patients, this

favourable response of treatment was not confirmed

(3,4)

The result of analysis on the significance of the mobility of

the spectrum of the pattern of tuberculin reaction in the immune

spectrum of tuberculosis related to the use of immuno-modula-

tor

(23)

, opens new prospects for the investigation whether immuno-

modulators given to subjects with chronic disease caused by

EBV, HTLV-I or HTLV-II can accelerate the achievement of

spontaneous cure or delay the progression of the immune status

of chronic disease (K-type) to the Lk-type of SADIS.

On the basis of the result of the advent of immuno-therapy

with BCG in tuberculosis patients following the achievement of

successful result of chemotherapy

(24)

, it is intriguing to speculate

that immuno-therapy with BCG given to subjects with chronic

disease caused by EBV, HTLV-I or HTLV-H following the

achievement of successful result of chemotherapy using effec-

tive drugs that hopefully will be made available, may stabilize the

achievement of cure.

B. The clinical management of diseases that emerge as

disease expression of the KK-type immune status (Lk-type of

SADIS) (fig. 4).

Unlike in patients with the Tb-type of SADIS, in patients

with the Lk-type of SADIS, primary malignancy as disease

manifestation of SADIS is located in tissues of various organs of

the host and tends to have a disseminated rather than a localized

character. Surgical resection of the disease is in general not

indicated as an effort to achieve complete remission of the lesion.

In patients with the adult T-cell leukemia as disease expression

of the Lk-type of SADIS due to HTLV-I, the result of treatment

with cytostatica is in general bad; remission is not observed or

only of short duration (quoted from: S. Daenan; Nederl. Tijdschr.

v. Geneesk. 1984, 128, 957-960). Aggressive treatment is con-

sidered necessary, but the "classical" combination regimens have

very little influence on the survival. Usually there is only a

response of short duration. Deoxycoformycine (DCF) has been

given to a petient with the adult T-cell leukemia with good result.

Complete remission was observed.

Other cytostatics for further eradication of the abnormal T-

cell (a combination of high dosage corticosteroids, cytarabine,

vincristine, doxorubicine and cyclophosphamide) were admi-

nistered following the achievement of complete remission in an

effort to "consolidate: this effect. A bone marrow aplasia de-

veloped following the use of the above combination treatment.

There was no development of relapse during a follow-up period

of 12 months and the patient remained in good health without

specific treatment (quoted from: S. Daenen, Nederl. Tijdschr. v.

Geneesk. 1984, 128, 957-960).

Treatment with interferon can be considered on the basis of

the probable viral genesis

(35)

. Deoxycoformycine (DCF) inhibits

specifically the adenosinedeaminase which leads to cumulation

of deoxyadenosine and deoxyadenosine triphosphate that are

toxic for the cell. A peculiar effect of the drug is that only

lymphocytes, in particular T-lymphocytes, are sensitive to DCF

(quoted from: S. Daenan: Nederl. Tijdschr. v. Heneesk. 1984.

128, 957-960).

Patients suffering from the hairy cell leukemia with sple-

nomegaly and pancytopenia should be treated by splenectomy.

Chemotherapy should be reserved for those patients that fail to

respond to splenectomy or that exhibit development of relapse

after a transient response to splenectomy

(36)

The non-Hodgkin's lymphomas are a heterogenous group of

malignancies which primarily involve lymphoid tissues. Radio-

therapy and/or chemotherapy are useful tools of management in

patients with NHL. A suitable lymph node, which emerges as a

single palpable lymph node, should be identified and the whole

node removed at operation with the minimum of trauma

(37)

. In

cases with single site involvement of bowel, i.e. at the ileocaecal

junction or the stomach, resection with bowel anastomosis is

indicated

(37)

. Histopathologic diagnosis is of essential impor-

tance for the choice of treatment and the prognosis of patients

with NHL. New diagnostic and therapeutic developments in the

last decades have shown that more patients with NHL can be

cured

(38)

. Beside histopathologic examination, immuno-pheno

typifying has also to be done in order to know whether the NHL

is of the B- or the T-cell origine

(39)

Patients in stage I or II are treated with radiotherapy on the

affected lymph node station or on the affected lymph node

stations (the socalled involved field radiation therapy

(39,40)

. The

disease-free 5-10 year survival is 60% and 50% respectively

(41)

This latter group of patients are likely cured

(39)

. The involved

field radiotherapy is hitherto the only curative treatment mo-

dality in patients with low grade non-Hodgkin's lymphoma in

stage I or II

(39)

Young age-group (< 40-60 year) and/or small

tumor mass are thereby the most important favourable prognostic

factors. More extensive radiotherapy, i.e. on more lymph node

stations, or combination therapy with chemotherapy, has not led

to an obvious improvement of the chance for the achievement of

cure

(39)

In patients with stage III and IV NHL, the follicular lym-

phoma is very sensitive to chemotherapy

(39,40)

. In 50-60% of

patients, complete remission is achieved and in 10-30% a good

partial remission is achieved with cytostatics like chlorambucil,

cyclophosphamide, or a combination therapy with cyclo-

phosphamide, vincristine and prednison (CVP). The advantage

of the combination treatment is that remission is achieved earlier

in the course of treatment

. The median duration of remission

is 2-3 years and afterwards treatment of relapse cases with the

socalled second line chemotherapy leads to remission of 23

years duration in 60-70% of the patients

(42)

. The mean duration

of survival in patients with low grade NHL in stage III or IV is 7

years.

Although the results of some investigations reveal a higher

remission-percentage and prolongation of disease-free interval,

the total survival duration with more intensive chemotherapy

does not appear to be prolonged

(43)

. Of much influence on the

prognosis is whether or not histologic transformation to a higher

degree of malignancy has taken place. In the course of the disease

this transformation occurs in 3040% of the patients. The

prognosis hereafter is bad. Despite aggressive chemotherapy,

the median duration of survival is only 1 year

(39)

. Long term treat-

ment with interferon-alpha appears to lead to remission in 40%

of patients with follicular lymphoma

@3>

At the moment examinations are done in several clinical

investigations to know whether addition of interferon-alpha to

conventional chemotherapy leads to improvement of the result of

treatment

(39)

. Chemotherapy is given to almost every patient

suffering from NHL located in the pancreas. Complete remission

during a minimal follow-up period of 18 months was observed in

50% of patients under treatment with chemotherapy as was

reported by de Jong et al.

(44)

Treatment of NHL of intermediate and high grade ma-

lignancy consists primarily of combination chemotherapy. In

some treatment schedule, radiotherapy is added as consolidation

treatment, but its additive value has still to be confirmed in an at

random investigation

(45,46)

. Patients with localized intermediate

grade lymphoma may be put under treatment with radiotherapy

alone, but apart from the large cell lymphomas, the risk of relapse

is high

(37)

Patients with stage IIIV large cell lymphoma are at present

treated intensively with combination chemotherapy. Complete

remission rate as high as 80% or more have been reported and as

many as 40% of patients are cured

(37)

. Patients with stage I

(1020% of all patients with an intermediate or high grade NHL)

can for the greater part (8090%) be cured with a limited number

of CHOP-courses (cyclophosphamide, doxorubicine, vincristine,

prednison) followed by involved field radiotherapy

(45,46)

In stage IIN, a remission percentage of 4060% is

observed with the standard treatment CJOP. With this treatment,

30% of all patients may be cured

(47)

Hodgkin's disease (HD) is a multifocal disease

(48)

. The

disease begins in a single lymph node followed by dissemination

to adjacent lymph nodes and then to other organs in a fairly

consistent pattern

(49)

. There are the lymphocyte predominance

and the lymphocyte depletion type in HD. Lymphocyte predomi-

nance type is observed in younger patients, is usually limited in

extent and has an excellent prognosis. Most investigators feel that

the lymphocyte-infiltrate found in HD lesion represents the

cellular immune response against the tumor and correlates with

a more favourable prognosis.

Lymphocyte depletion type is at the opposite end of the

spectrum, usually presenting with wide-spread disease and

constitutional symptoms and having a poor prognosis

(50)

Depletion of lymphocyte is comparatively rare in HD

(51,52)

Progression from lymphocyte predominance to lymphocyte

depletion is associated with worse prognosis

(53)

. The prognosis of

patients suffering from HD is markedly better than that of

patients suffering from NHL as was based on survival chances

(54)

There is no standard treatment in patients with HD

(55)

Radiotherapy is used in patients with HD; chemotherapy is at

least a component of treatment for advanced disease

(52)

. Since the

advent of radiotherapy and chemotherapy for treatment of pa-

tients suffering from HD, the prognosis is impressively im-

proved; 70% of the patients under treatment may even make

recovery

(51)

Both chemotherapy and radiotherapy eradicate the disease

under certain circumstances. At present time, the best approach

to treatment is to use either radiotherapy or combination chemo-

therapy alone in the appropriate stage

(48)

. Radiotherapy and

chemotherapy are also recommended for treatment of HD

(56)

. For

most patients with early HD (stages I-IIA), radiotherapy to a

mantle field remains the treatment of choice. Approximately

70% of patients will be cured using radiotherapy alone. Patients

in whom relapse develops are put under treatment with chemo-

therapy

(52)

It is unlikely that a tumor with a mass greater than five

centimeter in diameter can be sterilized and the dose of radiation

would have to be very high

(57)

. Patients with bulky mediastinal

lymph node enlargement are usually treated with chemotherapy

initially as are patients with advanced HD, many older patients

and those with B symptoms or unfavourable histology

(52)

Approximately 30% of patients have B symptoms as defined by

the Ann Arbor staging classification. B-symptoms include night

sweat, unexplained weight loss of more than 10% in 6 months

before diagnosis and fever of more than 38°C with no obvious

infection

(52)

Patients with advanced HD (stages IIB-IVB) should be put

under treatment with chemotherapy. Evidence reported by a

number of clinical trials now suggests, that adriamycin contain-

ing combinations should have a role in the primary treatment of

advanced HD. Adriamycin, bleomycin, vinblastine and dacarba-

zine (ABVD) have been used alone or in combination with

MOPP (mustine, vincristine, procarbazine, prednisolon) by a

number of centers, and existing data suggest that this may be

associated with improved cure rates

(52)

On account of the prolonged survival in patients that have

been put under treatment, late adverse reaction due chemo-

therapy may emerge, especially the development of neoplasia,

in particular the hematologic malignancies

(51)

Since the application of the megavolt apparatus and later the

polychemotherapy it is possible to obtain spectacular response

percentages, resulting in 8090% disease-free interval in the

early stages

(58,59)

and 6070% in the advanced stages of the

disease

(60)

. A child with HD should be treated primarily with

chemotherapy

(61)

Radiotherapy in children has important disadvantages.

Radiotherapy in the period of growth and development appears

to be able to bring about growth disturbances of the tissue under

treatment which results in misformation. Besides, secondary

tumor may develop following radiotherapy.

In a study on the efficacy of cytostatic therapy alone without

additional radiotherapy in children with HD of all stages,

Behrendt

(61)

has given to children with small (less than 4 cm)

lymph node tumors cytostatic therapy according to MOPP

scheme. Children with initially big (more than 4 cm) lymph node

tumors have been given the same cytostatic therapy plus involved

field radiotherapy as complementary therapy. The result of the

study revealed that of the 16 children treated with chemotherapy

alone, survival was 100% during follow-up periods ranging from

27 to 123 months (median 74 months). Recurrence-free survival

in this group of children amounted to 87.5%. The survival of the

14 children given additional radiotherapy amounted to 93%

during follow-up periods ranging from 26 to 92 months (median

58 months). Recurrence-free survival in this group of children

amounted to 85%. Behrendt

(61)

made the conclusion that a child

with HD should be treated primarily with chemotherapy.

The achievement of complete remission of disease mani-

festations of the Lk-type of SADIS means the achievement of

cure and the regression of immune status from the KK-type to the

K-type or even to the L-type, resulting in the augmentation of the

microbicidal activity of the macrophage. Like in the Tb-type of

SADIS, it can be expected that in the Lk-type of SADIS specific

chemotherapy against the causative organism (when available)

may be given following the achievement of complete remission

of the disease with chemotherapy and/or radiotherapy in order to

stabilize the cure. When specific chemotherapy against the

causative organism is not available, inoculation of BCG as

immuno-therapy may then be contemplated.

Bacillus Calmette Guerin was first tried by Mathd and

coworkers in patients that suffer from acute lymphocytic leukemia.

The attempt was based on the experimental observation that

drugs were not able to kill all the tumor cells and that other means,

such as immuno-therapy, were therefore considered necessary to

kill the residual leukemic cells

(31)

. Bacillus Calmette Guerin was

found to be effective in leukemic mice if the number of residual

malignant cells did not exceed 10

5 (31)

. The rationale behind the

above finding must be based not on the direct killing effect of

BCG but on the effect of BCG on the bactericidal effect of the

macrophage. Patients receiving weekly doses of BCG by

scarification for a total duration of 5 years following complete

remission of acute lymphocytic leukemia through the advent of

chemotherapy and radiotherapy (of the central nervous system)

appear to have responded best since 7 of 20 (35%) are still in

remission 19 years after initiation of treatment. In contrast, only

21 of 269 children (17.8%) receiving maintenance chemotherapy

alone survive for more than five years

(31)

Immuno-therapy with intradermal BCG (approximately 10

viable bacilli) following radiotherapy in patients with lymphoma

(stage IA and stage IIA) give rise to a lower incidence of relapses

and longer duration of remission

(31)

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Kegiatan Ilmiah

August 1618, 1994 7th ASEAN Congress of Plastic and Reconstructive Surgery

Bangkok

Information : Congress Secretariat,

Dept of Plastic Surgery, Siriraj Hospital,

Bangkok 10700, Thailand.