October - December 2004 Volume 13 Issue 04

INFECTIOUS

DISEASES

JOURNALPublished by the Infectious Diseases Society of Pakistan

of Pakistan

IDJ

ISSN 1027-0299

CONTENTS PAGE #

EDITORIAL

EditorM. Asim Beg

Co-EditorsZahra Hasan and Anita Zaidi

Ex-officio memberNaseem Salahuddin

Editorial Board

Oct - Dec 2004 . 91

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ORIGINAL ARTICLES

Assessment of Four Mortality Prediction Models in Intensive Care

Unit Patients with Sepsis.

Bushra Jamil, Kiran A. Qureshi, Maria Khan and Veerta A. Ujan.

Review Articles

Prevention of Transfusion Transmitted Malaria in an Endemic

Area– A Challenge for Blood Banks.

Bushra Moiz

Patterns of Tuberculosis Infections in the Central Nervous System.

Soobia Raza, Aliyah Sadaf, Faisal Fecto, Rushna Pervez Ali, Ehsan

Bari and S. Ather Enam

PerspectivesSUMO Vs VirusesWhat’s the Connection?

Romena Qazi

Case Report

A Young Man with Fever and Abdominal Pain.

Jawed Abubaker and Mariam Akram,

Bacteremia Associated with Central Line Infection by

Chryseomonas Luteola in a Case of Recurrent Meningiomas.

Muhammad Nasim Sabir, Bushra Jamil, Sajjad Ahmed

Photo Quiz

A 30 Year Old Asian Male with Right Sided Lower Abdominal

Pain and Fever.

Azizunnisa Raza, Rashia Ahmed, Nausheen Yaqoob and Shahid Pervez

News & Views

IDSP Activities

Instructions to Authors

Phagocytosis of M. tuberculosis by a macrophage

(Scanning Electron Micrograph Image Courtesy of Dr. Zahra Hasan)

92 . Infectious Diseases Journal of Pakistan

EDITORIAL

EDITORIAL

In this issue, we present an Original study by Jamil, B. et al. this discusses the assessment of four mortality prediction

models for patients in an ICU setting. Review articles discuss the very real dangers of transfusion transmitted malaria in an

endemic setting and patterns of tuberculosis infections of the central nervous system. The review on of tuberculosis meningitis

by Enam, A. et al. focuses on the diagnosis, clinical aspects and treatment of the disease. Pakistan has the eighth highest

tuberculosis burden in the world. Extra-pulmonary forms of tuberculosis are an increased cause of disease due to problems in

diagnosis of infectious such as, skeletal tissue, kidney, genitor-urinary tract and the brain. The causative agent of the disease is

mycobacterium tuberculosis, which resides in the macrophage (the primary defense cell of the host). Our cover image reflects

the uptake interaction between a mycobacteria and a macrophage host cell. In addition, improper screening of blood-by-blood

banks has become an issue of national importance. The government has recently shut down a number of blood banks in the

country. Efforts are being made to regularize blood-screening procedures. Moiz, B focuses on important considerations for

blood screening.

Our case reports are becoming more interactive and readers are encouraged to write to us with their views, letters or

news of developments in the field of infectious diseases.

This is the last issue for 2004 (OCT-DEC) and we will be formally applying for International indexing. The editorial

board is reflecting change and we have invited leading international experts to come on board. The IDJP is the symbol of the

Infectious Diseases Society of Pakistan and we look forward to raising our standards in the quest for international recognition.

This issue also leads up to the ISDP Annual National Conference; the 2nd

National Conference on Infectious Diseases

which will be held in Lahore 25-27 March, 2005. We look forward to seeing you in Lahore!

The Editors

Oct - Dec 2004 . 93

ORIGINAL ARTICLE

Corresponding author: Bushra Jamil, Assistant Professor, Dept. ofMedicine, Pathology and Microbiology, The Aga Khan UniversityHospital, Stadium Road, Karachi, Pakistan.Email: bushra.jamil@aku.edu

Assessment of Four Mortality Prediction Models in Intensive Care Unit Patients with Sepsis

Bushra Jamil, Kiran Alam Qureshi, Maria Khan, and Veerta Ali Ujan.

Departments of Medicine, Pathology and Microbiology,

The Aga Khan University Hospital, Karachi, Pakistan.

Abstract

Early recognition of sepsis and the rapid institution of

therapy are absolutely essential for appropriate management of

patients admitted to the hospital. Both score-generating clinical

tools and clinical acumen are important for identifying the sick,

while early intervention in acute deterioration is beneficial,

before and after ICU admission. Several scoring systems have

been devised which attempt to identify risk factors and predict

outcome of different patient groups. The purpose of this pilot

study was to assess the value of four mortality risk scoring

systems, i.e. Mortality Probability Models (MPM) - admission,

MPM -24 hours, Simplified Acute Physiology Score (SAPS)

II and Acute Physiology and Chronic Health Evaluation

(APACHE) II, in predicting outcome in patients admitted to

the intensive care unit with sepsis. The expected outcome was

calculated according to the specifications of each system and

was compared to the actual outcome.

Key words

Mortality risk prediction models, sepsis

Introduction

Infections are a leading cause of morbidity and mortality

in Pakistan. Delay in diagnosis of serious infections and

inappropriate or inadequate management lead to the development

of systemic inflammatory response, followed by septic shock

and death. Proper management of individual patients demands

early recognition, accurate etiological diagnosis and appropriate

treatment. In sepsis, the extent and involvement of different

organ systems has been shown to affect outcome. This

observation may allow the clinician at the bedside to recognize

and respond early to adverse patterns and changes of organ

system dysfunction in septic patients. Such an assessment can

be facilitated and made more objective through the use of

mortality prediction models. While several systems or models

have been designed for intensive care unit (ICU) patients, there

are some models which can be applied to non-ICU patients,

who are not monitored invasively.

We conducted this pilot study to assess four mortality

prediction models in our patients with sepsis. Various clinical

and laboratory parameters were studied in patients admitted to

the ICU with severe sepsis and septic shock. The outcome

predicted by calculations defined in the models was compared

with the actual outcome, in order to assess the reliability and

utility of these systems in predicting outcome of sepsis.

Methods

Case records of 20 patients who were admitted to the

ICU with the diagnosis of sepsis, over a period of 3 months in

the year 2000, were studied retrospectively. Five patients had

to be excluded because of insufficient data. The patients were

selected randomly and based on the data available, were analyzed

according to the following scoring systems: Mortality Probability

Models (MPM) - admission, MPM -24 hours, Simplified Acute

Physiology Score (SAPS) II and Acute Physiology and Chronic

Health Evaluation (APACHE) II. Inclusion criteria included

age >18 year, signs and symptoms of local infection (cellulitis,

septic arthritis, LRTI, UTI) or body temperature >38oC or <

36oC orally with one of the following: hypotension, defined as

systolic blood pressure <90 mmHg or its reduction by >40

mmHg from patient’s baseline, in the absence of other causes

for hypotension, tachycardia defined as a pulse rate >90 beats

per minute, tachypnea defined as respiratory rate >20 breaths

per min or PCO2 <32 torr, white blood cell count >12,000

cells/cumm or <4000 cells/cumm, or with a differential count

showing >10% band neutrophil forms.

Exclusion criteria included age less than 18 years,

admission due to extensive burns and coronary artery disease.

Presence of significant coexisting illnesses was noted. The

expected outcome was calculated on line at the official website

of French Society of Anesthesia and Intensive Care (sfar.org),

according to the specifications of each system. The predicted

death rate was compared with the actual outcome of sepsis in

each patient. Sensitivity, specificity and positive predictive

value of each system were also determined.

Results

The study patients included 11 males and 5 females.

Age ranged from 18 to 79 years with a mean of 52.1 years.

Females were slightly older with a mean age of 57.4 years;

mean age for males was 46.8 years. Most of the patients had

more than one significant associated illnesses (table 1).

94 . Infectious Diseases Journal of Pakistan

Diabetes mellitus was the commonest associated illness

followed by renal failure and chronic liver disease. A significant

number of patients had more than one co-morbid conditions

concomitantly. Three patients did not have any underlying

illnesses; one of them was 27 weeks pregnant. Infections of the

skin and soft tissues, including cellulitis and necrotizing fasciitis

were the commonest infections preceding sepsis and septic

shock; pneumonia was also common (table 2). Ten patients

expired (66.6%), 3 recovered from their illness and outcome

of 2 patients who were transferred to another facility could not

be ascertained.

Table 2. Site of infection in patients with sepsis

The sensitivity and specificity of all the scoring systems

were calculated and results are shown in table 3. The sensitivity

of APACHE II for predicting mortality was 100% at the score

of >22 which translates into a predicted death rate of >42.4.

For the rest of the scoring systems, sensitivity ranged from 77

to 87%. Specificity was highest at 55.5% for SAPS II.

Table 3. Sensitivity, specificity and positive

predictive value of mortality prediction models

Discussion

Severe sepsis and septic shock are major reasons for

hospital and intensive care unit admissions. Data from the Aga

Khan University Hospital shows that over the last 15 years, the

overall mortality due to sepsis has remained around 36.6%.

Mortality rate in patients with septic shock has been a staggering

81%. This is excessive in comparison mortality rates ranging

from 40-60% quoted in literature1,2 . In critically ill patients

in the intensive care unit (ICU) who are already compromised

because of coexisting serious co-morbidities, septic shock may

be associated with higher mortality3. It has been shown that

the systemic inflammatory response to severe infection evolves

in stages from sepsis to severe sepsis to septic shock with

corresponding increases in the proportion of patients with

positive blood cultures, end organ failure and crude mortality4.

It is logical to presume that the progression of sepsis and 28-

day mortality may be influenced by effective early interventions5.

Even those patients who have developed end organ damage

and shock might benefit from early identification and rapid

support. Studies have shown that the crude mortality of all

patients in an intensive care as well as that for patients with

septic shock in an ICU decreases if physicians remain in the

hospital and are supervised by subspecialists trained in critical

care 6,7

. The ability of the highly skilled ICU personnel and the

ability of the sophisticated patient monitors would be expected

to have detected the onset of shock at an earlier point in time.

Additionally, the ICU has highly skilled physicians, nurses and

support personnel who have the ability to evaluate patients

more frequently with continuous assessment of vital signs. The

typical ICU patient is monitored with sophisticated equipment

which is expected to alert the ICU staff to critical alterations

in the patient’s clinical status. The result would be earlier

detection and treatment of septic shock. In contrast, general

ward patients do not have access to the same frequency or

intensity of assessments and monitors, resulting in delays in

the detection of shock onset3. The prolonged period of

hypoperfusion of critical organ beds, such as liver, brain, heart,

kidney and gastrointestinal tract may give rise to multiple organ

dysfunction and failure, which is associated with a high rate of

morbidity and mortality 8.

Scoring system Sensitivity (%) Specificity (%) PPVa

APACHE II 100 at score of >22 45.4 0 . 4 5

SAPS II 87.5 at score of >39 55.5 0.636

MPM admission 80 at score of >20 50 0.727

MPM 24 h 77.7 at score of >19.4 42.8 0.636

apositive predictive value

Co-morbid conditions N (%)

Diabetes mellitus 6 (40)

Renal failure (acute and chronic) 5 (33.3)

Chronic liver disease 4 (26.2)

Hematological disorders a

3 (20)

IHD/CMPb

2 (13.3)

Gut perforation 2 (13.3)

NHLc

1 (6.6)

Elephantiasis 1 (6.6)

Mitral incompetence 1 (6.6)

Hypertension 1 (6.6)

Liver abscess 1 (6.6)

Diverticular disease 1 (6.6)

Table 1. Significant coexisting illnesses in sepsis patients

aAcute lymphocytic leukemia (2) aplastic anemia (1)

b Ischemic heart disease/ cardiomyopathy

c Non-Hodgkin lymphoma

Site of infection N (%)

Skin and soft tissues 6 (40)

Lung 4 (26.2)

Gut perforation 2 (13.3)

Urinary tract 1 (6.6)

Endocarditis 1 (6.6)

Encephalitis 1 (6.6)

Oct - Dec 2004 . 95

In septic patients, the number of organ systems with

impaired function is important because it correlates with clinical

outcome 9,10,11

. It has been shown that the pattern and evolution

of organ system dysfunction over the first 3 days of sepsis is

significantly related to 30-day mortality 12

. This observation

may potentially allow the clinician at the bedside to recognize

and respond early to adverse patterns and changes of organ

system dysfunction in septic patients. Clinical assessment can

be facilitated and made even more objective through the use

of mortality prediction models. While such systems have been

designed for ICU patients, some of these can easily be applied

to non-ICU patients, who are not monitored invasively.

However, debate still continues about the accuracy of

these scoring systems, their efficiency in assessing the severity

of illness and whether they have a prognostic role in the

estimation of the illness outcome. Additionally, these tools have

to be validated in the population in question before they are

adopted for outcome prediction and decision making.

We studied Mortality Probability Models (MPM) -

admission, MPM -24 hours, Simplified Acute Physiology Score

(SAPS) II and Acute Physiology and Chronic Health Evaluation

(APACHE) II to assess their utility in predicting mortality in

our patients.

It has been emphasized that the calculation of a risk

assigned to a measured score is an epidemiologic tool, and

should not be used as a single patient prevision tool. However,

sequential calculations may be of immense importance in early

recognition of deterioration and the need for more aggressive

intervention in patients who present at an early stage of sepsis.

Through early diagnosis and intervention, we may be able to

decrease mortality associated with sepsis and septic shock in

our patient population.

In the current study, we recruited ICU patients only

because of variables in APACHE II system. MPM- admission,

MPM-24 hours and SAPS II could be used in non-ICU patients

as well. Most of the patients in our study had serious concomitant

illnesses, which could have contributed to mortality. While

APACHE II correctly predicted mortality above a certain score,

and proved to be the most sensitive of the models studied,

SAPS II was the most specific system for this purpose. The

other systems too performed reasonably well, although

calculations on sensitivity, specificity and positive predictive

value may not be entirely reliable with a small sample size.

There is a need to study the utility of these models in

early recognition of sepsis-related complications in a large

cohort of our patient population, before recommending them

as essential tools for bed side evaluation of patients with sepsis.

References

1. Bone RC. Gram negative sepsis: Background, clinical

features, and intervention. Chest 1991;100:802-808

2. Parrillo JE, Parker MM, Natanson C, et al. Septic

shock in humans: Advances in the understanding of

pathogenesis, cardiovascular dysfunction, and therapy.

Ann Intern Med 1990;113:227-242

3. Balk RA. Outcome of septic shock: Location, location,

location. Crit Care Med 1998; 26:983-984

4. Rangel-Frausto MS, Pittet D, Costigan M, et al. The

natural history of systemic inflammatory response

syndrome (SIRS). A prospective study. JAMA 1995;

273:117-123

5. Lundberg JS, Perl TM, Wiblin T, et al. Septic shock:

An analysis of outcomes for patients with onset on

hospital wards versus intensive care units. Crit Care

Med 1998; 26:1020-1024

6. Li YC, Phillips MC, Shaw L, et al. Onsite physician

staffing in a community hospital intensive care unit.

Impact on test and procedure use and on patient

outcome. JAMA 1984; 252:2023-2027

7. Reynolds HN, Haupt MT, Thill-Baharozian MC, et

al. Impact of critical care physician staffing on patients

with septic shock in a university hospital medical

intensive care unit. JAMA 1998; 260:3446-3450

8. Swank GM, Dietch EA. Role of gut in multiple organ

failure: Bacterial translocation and permeability

changes. World J Surg 1996;20:411-417

9. LeGall JR, Lemeshow S, Leeu G, et al. Customized

probability model for early severe sepsis in adult

intensive care patients. JAMA 1995; 273: 644-650

10. Marshall JC, Cook DJ, Christou NV, et al. Multiple

organ dysfunction score: A reliable descriptor of a

complex clinical outcome. Crit Care Med 1995;

23:1638-1652

11. Vincent JL, Moreno R, Takala J, et al. The SOFA

(sepsis- related organ failure assessment) score to

describe organ dysfunction/failure. Intensive Care Med

1996; 22:707-710

12. Russell JA, Singer J, Bernard GR, et al. Changing

pattern of organ dysfunction in early human sepsis is

related to mortality. Crit Care Med 2000; 28:3405-

3411

96 . Infectious Diseases Journal of Pakistan

REVIEW ARTICLE

Prevention of Transfusion Transmitted Malaria in an Endemic area– A Challenge for Blood Banks

Dr. Bushra MoizDepartment of Pathology and Microbiology,Aga Khan University Hospital, Karachi. Pakistan.

Background:

Malaria is one of several blood borne infections that

are transmitted through transfusion of blood. The disease is

caused by Plasmodia, of which two species vivax and falciparum

are prevalent in Pakistan. Transmission of this parasite through

blood transfusion is important as only a small number of infected

red cells from donor can lead to malaria in the recipient.

Moreover, the diagnosis is often missed and unexpected in a

patient who is otherwise critically sick. This may be life

threatening in extreme cases, especially if the species is

Plasmodium falciparum.

The first case of transfusion malaria was reported in

19111. Since then increasing number of cases have been reported

world wide. The risk of acquiring malaria through transfusion

is dependent on incidence and prevalence of the disease at a

particular area. In countries like USA and Canada, where

malaria is not endemic the incidence is as very low2. The annual

incidence reported by US Center for Disease Control (CDC)

is only 1 -3 cases per year3. However, in endemic countries like

ours, the rate of transmission may be as high as 50 cases per

million blood donation1. We do not know the actual prevalence

of transfusion transmitted malaria in Pakistan. The incidence

was reported to be nil by Rahman M et al in 2003 from Punjab4.

However, this appears to be an underestimation of overall

burden of transfusion malaria that can be measured only through

a comprehensive national surveil lance program.

In a country like ours where malaria is endemic, there

is a need of screening every donor through proper laboratory

tests to alleviate the chances of post transfusion malaria.

Laboratory screening for Transfusion-transmitted Malaria

National Institute of Health (NIH) consensus

conference in 1995 requires that every donor blood should be

screened for various infections including HIV, Hepatitis B and

C, malaria and syphilis5. However, there is no suitable test yet

available for screening malaria in the donors. The different

diagnostic tests available for malaria include examination of

peripheral smear, QBC, various serological tests including PCR.

However, all of these tests have their limitations in terms of

specificity, sensitivity and cost effectiveness. Hence, it the

challenge for a blood bank to properly screen the donated bloodfor malaria by a test which should be simple, sensitive, fastand at the same time economically feasible also.

Various strategies for Screening Malaria:

1. Donor history: A report prepared by WHO in 1998 statedthat the most effective way of screening donors is to take properhistory of malaria or fever that could be due to malaria

6. Donor

selection criteria should be designed to exclude potentiallyinfectious individuals from donating red cells. However, theinfected donor may have a very low parasitemia; he may nothave a clinical history of recent past or present history of febrileillness

7. Thus, there are good chances that he may pass out

through donor screening process. Further more, the acquiredimmunity in adults in malaria endemic areas may result in lowgrade parasitemia without symptoms

8. Such carriers can also

be difficult to identify on history basis alone.

Federal Drug Administration (FDA)9 and American

Association of Blood Bank (AABB)10

had set the followingcriteria for donors who have traveled to or lived in an endemicarea:

1. Travelers may donate blood 6 months after returningfrom endemic areas provided they are free of symptomsand have not taken anti-malarial drugs.

2. Persons with past history of malaria should be deferredfor 3 years after becoming asymptomatic.

3. People who had been on chemoprophylaxis can donateblood after 3 years of stopping their therapy.

4. Immigrants or visitors from endemic area can be accepted as donors 3 years after departure if they areasymptomatic.

5. Proven carriers of malaria or persons who had malariadue to P malariae are excluded permanently from donating blood.

The 3 years limit has been established because infectionwith the relapsing forms of malaria (Plasmodium vivax andPlasmodium ovale) rarely persist for more than 3 years aftera naturally acquired infection. Infection with Plasmodium

falciparum usually has clinical malaria with in 3 months butmay show asymptomatic infection for a year or more.Plasmodium malariae may remain undetected in blood forseveral years.

However, these deferral policies are not practical for

endemic areas as exclusion would include nearly all the donors11

.

Corresponding author: Bushra Moiz,Assistant Professor, Department of Pathology & Microbiology,Aga Khan Universi ty Hospital , Karachi 74800E mail address:bushra.moiz@aku.edu

Oct - Dec 2004 . 97

Furthermore, it is not always possible to obtain accurate travel

and immigration history. Some cases of transfusion transmitted

malaria would always occur because of occasional asymptomatic

persistence of malarial parasites.

2. Examination of Peripheral film:

The gold standard for malaria diagnosis is peripheral

film examination. However, this is very labor intensive and

skill effective. The reason is that the asymptomatic blood donors

have very low levels of parasite count12

and sensitivity of

peripheral film microscopy declines in parallel with the density

of malarial parasites in the blood11

. Thus, microscopy of blood

films involving a large numbers of blood donors on daily basis

seem to be impractical.

3. QBC:

It is another method of identifying the malarial parasites

in the peripheral blood. It involves staining of the centrifuged

and compressed layer of red cell layer with acridine orange and

its examination under UV light source13

. It is fast and more

sensitive than smear examination and can detect parasites even

less than 100/ul14

. However the test is non specific and stains

nucleic acid from all cell types and therefore technically

demanding15

. The major disadvantage is that it requires costly

equipment and consumables13.

4. Automated analyzers:

Some hematology cell counters detect parasites by

giving abnormal signals that are produced by hemozoin in white

cells 16. Hemozoin is the pigment produced by the parasites as

a breakdown product of hemoglobin present in host red cells.

As the red cells rupture, they release hemozoin which is engulfed

by phagocytic cells like neutrophils and monocytes. Initial

studies have shown good results in terms of sensitivity and

specificity 17

. But its value in donor screening is yet to be

evaluated as parasitemia and production of hemozoin is lower

in them.

5. Rapid diagnostic tests:

Immunochromatographic tests are based on the

detection of parasite antigens from the peripheral blood using

either monoclonal or polyclonal antibodies against the parasite

antigen targets. Currently these tests capture histidine rich

protein II, a pan malaria aldolase and parasite specific lactate

dehydrogenase15

. The rapid diagnostic tests are simple, user

friendly not requiring skilled technologists and equipment.

These tests usually have a sensitivity of 35-97% for

P falciparum and 2-97% for P vivax or non-falciparum species18

.

There is also a possibility of false positive and false negative

results with these tests15

. The sensitivity of these tests is

considerably less at low levels of parasitemia and non immune

individuals.

These assays may serve as a promising test for

screening our donors. But there is a need to develop the devices

so that they may have high acceptable sensitivity and an

affordable cost.

6. ELISA:

It is an interesting alternative for the screening of

blood donors. It is automated with fast through put and

compatible with other transfusion screening procedures.

However, the test lacks sensitivity as the low levels of antibodies

cannot be detected by this method 19. A study done recently

demonstrated that combined detection of antigens and antibodies

may represent a sensitive strategy for the testing of blood

donors20

. More trials are required before ELISA can be accepted

as a valuable option for this purpose.

7. PCR:

The major advantages of using a PCR based technique

are its high sensitivity as it can detect parasites as low as 5 or

less per µl of blood 21

and identification of species22

. Rubio et

al in 1999 found semi nested PCR to be very useful for screening

donors at risk who were immigrants in Spain23

.However, the

test may be positive after successful treatment of malaria as

PCR can detect DNA from non viable parasites also24

. Hence,

PCR testing in endemic areas will result in false positive results

with too much loss of donated blood. The other associated

problems are its prolonged time frame and cost in-effectiveness.

The cost of screening through PCR was estimated to be

$3,972,624 per case of malaria averted 25

.

Although PCR technique is very promising for the

screening of malaria, but still it can not be considered as a

method of choice for our purpose. The future advances in PCR

technique may help to overcome the problems of cost and

timings.

Conclusions:

Transfusion associated malaria is often severe and

fatal. The detection of infected donor is difficult in endemic

areas due to the lack of suitable screening test. Deferral of

donors based on history is not practical for endemic areas.

Blood smear staining techniques show poor results due to the

low parasite concentration in many asymptomatic blood donors.

Antibody detection test is not helpful because of universal

presence of the antibodies in healthy donors in malaria endemic

areas. Malarial antigen test seem to be promising but more

costly. PCR technique, although is the most sensitive test is not

economically feasible and impractical also because of its

prolonged duration.

98 . Infectious Diseases Journal of Pakistan

It is highly amenable that sensitive tests which are simple, fast,

cost effective should be introduced for malaria screening in

blood donors.

References:

1. Bruce-Chwatt. Transfusion malaria revisited. Trop

Dis Bull 1982;79:827-40

2. Slinger R, Giulivi A and Bodie-Collin M et al.

Transfusion- transmitted malaria in Canada. Can Med

Ass J 2001, 164(3): 377-379.

3. Mungai M, Tegtmeier G, Chamberland M and Parise

M. Transfusion- transmitted malaria in the United

States, from 1963 through 1999. New Eng J Med

2001;344(26):1973-8

4. Rahman M, Akhtar GN, Rashid S and Lodhi Y. Risk

of Malaria transmission through blood transfusion

and its detection by serological method. Pak J Med

Sci 2003, 19(2): 106-110

5. Infectious disease testing for blood transfusions. NIH

Consensus Panel on Infectious Disease Testing for

blood transfusions. JAMA 1995;274(17): 1374-9

6. Strategies for Safe Blood transfusion.

7. Transfusion malaria: serological identification of

infected donors-Pennsylvania, Georgia. MMWR

1983;32(17):2224

8. Bjorkman A, Perlman H, Peterson E, Hogh B,

LabbadM and Warsane M et al. Consecutive

determination s of sero activities to Pf 155/RESA

antigen and to its different repetitive sequences in

adult men from a holo endemic area of Liberia.

Parasitol Immunol 1990;12:115-23

9. Zoon K. Recommendations for deferral of donors for

malaria risk: letter to all registered blood

establishments. Washington DC. Food and drug

administration, July 1994.

10. Standards for blood banks and transfusion services.

19th ed. Bethesda, Md: American Association of blood

banks, 1999.

11. Saeed AA, Rasheed AM, Naseer IA. Onazizi MA,

Kathani SA and Dubois L. Malaria screening of blood

donors in Saudi Arabia. Annals of Saudi Medicine

2002; 22(5):32932

12. Choudhury N, Jolly JG, Mahajan RC, Ganguly NK,

Dubey ML and Agniho SK. Malaria screening to

prevent transmission by transfusion: an evaluation of

techniques. Med Lab Sci 1991;48(3):206-1113.

14. Wongrichanalai C, J Pornsilapatip and V

Namsiriponpun et al. Acridine orande Flourescent

microscopy and detection of malaria in populations

with low-density parasetemia. Am J Trop Med Hyg

1991;44:17-20

15. Moody A. Rapid diagnostic tests for malarial parasites.

Clin Microbiol Rev 2002; 15: 66-78

16. Haenscheid T, Pinto BG, Cristino JM and Grobusch

MP. Malaria diagnosis with the hematology analyzer

CELL-DYN 3500. What does the instrument detect?

Clin Lab Hem 2000;22:1-4

17. Scott CS, Zyl DV and Ho E et al. Automated detection

of WBC intracellular malaria –associated pigment

(Hemozoin) with Abott Cell DYN 3200 and Cell DYN

3700 Analyzers: Overview and results from the South

African institute for medical research (SAIMR) II

evaluation. Lab Hem 2002; 8:91-101.

18. Murray CK, Bell D, Gasser RA and Wongrichanalai.

Rapid diagnostic testing for malaria. Trop Med and

Int Health 2003;8(10):876-83

19. Assal A, Kauffmann LC and Rodier MH et al.

Comparison of two techniques for the detection of

Plasmodium falciparum antibodies, falciparum-

spot IF (bio merieux) and Malaria IgG Celisa (BMD):

preliminary results. Transf Clin Biol

1999;6:119-23.

20. Silvie O, Thellier M and Rosenheim M et al. Potentila

value of Plasmodium falciparum-associated antigen

and antibody detection for screening of blood donors

to prevent transfusion transmitted malaria. Trans

2002;42:357-62

21. Snounou G, S Viriyakosol, W Jarra, S Thaithong and

KN Brown. Identification of the four human malarial

species in fields samples by Polymerase chain reaction

and detection of high prevalence of mixed infections,

Mol Biochem Parasi tol 1993,58: 283-92

22. Rubio JM, Post RJ, Leeuwen WH, Henry MC,

Lindergard G and Hommel M. Alternative polymerase

chain reaction method to identify Plasmodium Species

in human blood samples: the semi-nested multiplex

malaria PCR (SnM-PCR). Trans R Soc Trop Med Hyg

2002; 96(1): 199-204

23. Rubio JM, Benito A and Berzosa PJ et al. Usefulness

of seminested multiplex PCR in surveillance of

imported malaria in Spain. J Clin Microbiol 1999; 37:

3260-4

24. Srinavasan S, AH Moody and PL Chiodini.

Comparison of blood film microscopy, the Optimal

dipstick, Rhodamine 123 and PCR for monitoring anti

malarial treatment. Ann Trop Med Parasitol 2000; 94:

227-32

25. Shehata N, Kohli M and Detsky A. The cost

effectiveness of screening blood donors for malaria

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Oct - Dec 2004 . 99

REVIEW ARTICLE

Introduction

Tuberculous involvement of central nervous system(CNS), although not very frequent, results in severe morbidity. Tuberculosis (TB) is endemic in developing countries but evenin developed countries, after an initial decline up until 1980’s,incidence of TB is on the rise. The AIDS epidemic, emergenceof multi-drug resistant strains and immigration of people fromendemic areas are some of the factors significantly contributingto this increase. Consequently, the burden of central nervoussystem tuberculosis has increased significantly worldwide.

Infection of CNS by tuberculosis (TB) can developin several patterns. The old adage “Syphilis - the GreatMasquerader”, probably applies to tuberculosis as well whenit involves the central nervous system. This poses a constantchallenge to the clinicians in making a definitive diagnosis.The various extra-pulmonary manifestations of tuberculosisand the multitude of organs involved complicate the task further.Central nervous system (CNS) tuberculosis forms a significantproportion of extra-pulmonary tuberculosis

1. In most cases,

infection is thought to spread hematogenously. Due to a lackof reliable diagnostic tests and due to morbidity inherent insurgical procedures for diagnosis, the decision to treat centralnervous system tuberculosis is done empirically in most endemicareas. Thus its purulent to be cognizant of the patterns of CNSinfection by TB.

There are four major patterns of CNS TB:

1- tuberculous meningitis (TBM)2- tuberculomas in brain and spinal cord (TBT)3- tubercular brain abscess (TBA)4- tuberculous encephalopathy (TBE)

Tuberculous Meningitis

The most common form that tuberculosis takes in thecentral nervous system is TBM. This is characterized byaccumulation in the meninges of gelatinous exudates commonlyaffecting the cranial nerves. This exudate is composed ofmononuclear cells, epithelioid cells and Langhans’ giant cells.It usually arises from subependymal regions from small caseousfoci known as “Rich” foci (Greenfield). Copious exudates ofTBM may cause obstruction in CSF flow at the level of basal

Corresponding Author: S. Ather Enam, MD, PhD, FRCSI,FRCSC, FACS Head, Section of Neurosurgery and AssociateProfessor,The Aga Khan University, Karachi, PakistanE-mail: ather.enam@aku.edu

Patterns of Tuberculosis in the Central Nervous System

Soobia Raza1, Aliyah Sadaf1, Faisal Fecto1, Rushna Pervez Ali1, Ehsan Bari2, S. Ather Enam2

The Aga Khan University Medical College1, Section of Neurosurgery2, Aga Khan University Hospital, Karachi.

cisterns (basal arachnoiditis) resulting in communicating

hydrocephalus (Figure 1). An incidence of hydrocephalus as

high as 80% in tuberculous meningitis has been reported.

Accumulation of exudates in the basal regions may compress

optic chiasm, nerves and internal carotid arteries. Opto-

chiastmatic arachnoiditis can lead to blindness in 5-10% of

cases with TBM. Patients with tuberculous meningitis are

clinically staged according to their presenting symptoms

and their stage at diagnosis correlates directly with individual

prognosis (Table 1).

Figure 1. MR image in a case of tuberculous meningitis.

Coronal cut showing enhancement of the meninges in the left Sylvianfissure (a) and basal meninges (a,b). Resultant hydrocephalus is alsoevident in the MR images particularly in (b)

(a)

(b)

100 . Infectious Diseases Journal of Pakistan

Table 1

In many developing countries tuberculous meningitis

is especially common in patients younger than 5 years. Infants

usually present with non-specific symptoms, which include

irritability, restlessness poor feeding, and physical signs of

hydrocephalus. In immunocompromised patients, tuberculous

meningitis manifests clinically in a similar manner. That TBM

complicates a significant number of TB in developing countries

and that TBM incidence is increasing progressively compared

to other extra-pulmonary TB even in developed countries is

shown in Figure 2.

Two other conditions that need to be considered withTBM are tuberculous vasculitis and tuberculous encephalitis

4.

The exudative inflammatory change in the meninges mayextend along the perforating vessels and incite reactiveproliferation of microvessels. This extension can give rise toencephalitis which may or may not be focal. Vasculitis maycause thrombosis in the perforating and other small vessels andoccasionally in larger vessels such as middle cerebral arteryleading to ischemic changes and multiple infarcts, one of themain perilous outcomes of TBM.

Tuberculomas

A tuberculoma is an infrequent manifestation of centralnervous system tuberculosis. It may occur singly but is moreoften multiple. In approximately 16% of patients, it may co-exist with culture positive tuberculous meningitis

5. At Aga

Khan University Hospital (AKUH), Karachi, Pakistan 246patients were admitted during the period of 2000-2004 withthe suspicion of tuberculous meningitis. 89 (36.1%) of thesehad tuberculomas, either with or without culture positivetuberculous meningitis (unpublished observations).The most common site for TBT is posterior cranial fossa(Figure3).

Figure 2b

16.00%

14.00%

12.00%

10.00%

8.00%

6.00%

4.00%

2.00%

0.00%1969-1973 1975-1990 1990 1995 onwards

Tuberculousmeningitis as% ofextrapulmonary tuberculosis

Figure 3

No of new cases oftuberculousmeningitis/100,00population

No of new cases oftuberculosis/100,000 population

2500

2000

1500

1000

500

0Africa Asia US Europe

Figure 2a

TUBERCULOUS MENINGITIS

INTRACRANIAL TUBERCULOMA

TUBERCULAR BRAIN ABSCESS

Constitutional symptoms

Headache

Meningism

Carnial nerve palsies

Altered mental status, Focalneurological deficits, nvulsions

80%

86%

25-30%

15-40%

S/s of space occupying lesion

i.e. headache, seizures

Focal neurological deficits

S/s of raised intracranial pressure

Fever, signs of meningeal irritationand cranial nerve palsies lesscommon

60-100%

33-68%

56-93%

Constitutional symptoms

Headache

Focal neurological deficits

Seizures

Altered consciousness

46%

47%

71%

35%

24%

(3a)

(3b)

Oct - Dec 2004 . 101

The reason for this is not well understood but might

be the predilection of TBM to occur in basal regions which

eventually gives rise to TBT. Posterior fossa location of TBT

is particularly more common in patients less than 20 years.

Compression of the CSF pathway either in the 4th ventricle or

at the cerebral aqueduct by tuberculomas gives rise to

hydrocephalus. Microscopically, it is composed of a caseous

center surrounded by a granulomatous reaction including giant

cells, lymphocytes and fibrosis. Unusual presentations of TBT

may consist of multiple small perivascular “incipient type”

granulomas which develop as gradual conglomeration on cortical

surface, miliary neuro-tuberculosis, cystic tuberculomas, and

tuberculomas in subdural or trans-dural locations6. Tuberculomas

were one of the most common space occupying lesions in the

beginning of the twentieth century. Their incidence dropped

to less than 2% during the latter half of the same century in

developed countries but it continues to constitute a significant

proportion of intracranial mass lesions in developing countries

(8-12%)7. The clinical features of intracranial tuberculomas

are related to the mass effect, local or general, produced by the

lesion (Table 2).

Tuberculomas in the spinal cord may present with

signs and symptoms of myelopathy spinal cord compression,

or rarely radiculopathy8.

Tubercular Brain Abscess

TBA is a rare form of central nervous system

tuberculosis. It is characterized by an encapsulated collection

of pus, containing viable tubercular bacilli with or without

evidence of tubercular granuloma9. Not more than 25 cases

have been reported so far in literature. They are typically larger

than tuberculomas and evolve rapidly. The exact mechanism

of their formation is unknown. Occasionally tuberculomas may

contain super-infection by other bacteria10

. The signs and

symptoms due to TBA may not be much different than those

from TBT except for its fast progression (Table3).

Table 3

Tuberculous Encephalopathy

TBE is another rare outcome of TB invading CNS.It is usually more common in younger population and ischaracterized by diffuse brain edema and demyelination whichusually is extensive11. Microscopically it is characterized bymicrovascular necrosis with perivascular macrophage reactionand demyelination along with focal glial nodules in the whitematter and occasional hemorrhagic lesions. Combination ofprogressive tuberculosis along with severe alcoholic intoxicationahs been characterized as acute toxic encephalopathy syndrome

12.

This syndrome is characterized by impaired consciousness,epileptic seizures, disseminated intravascular coagulation, signsand symptoms of meningitis without spinal fluid changes. Thissyndrome may be one of the leading causes of neurologicdevastation and death in CNS TB patients with high alcoholintake.

Spinal tuberculosis (Pott’s disease), the most commonform of skeletal tuberculosis will be mentioned here briefly asit frequently leads to neurologic deficits. It may result in seriousconsequences like deformity and paraplegia due to bonydestruction. TB spine may also lead to epidural tuberculousabscess or less commonly subdural tuberculous abscess. Anincreased predominance of spinal TB in immunocompromisedindividuals has been noted. Chemotherapy is the mainstay oftreatment, with surgical procedures reserved for cases whichare medically untreatable.

Diagnosis

Both TBT and TBA remain difficult to diagnose andrapid-turn around testing with high predictive values is needed.Clinical features supported by indirect evidence such as CSFexamination and imaging studies of the head and spine havebeen used for early diagnosis. The differentials to be considered

TABLE 2

Staging of Patient with TBM (Ref 35)

STAGING CLINICAL MANIFESTATIONS

Stage 1 Fully conscious, no focal neurological deficits

Stage 2 Inattentive, confused, focal neurological signs

Stage 3 Coma, stupor, multiple cranial nerve palsies,

hemiplegia or paraplegia

Predictors of Poor Prognosis in CNS TB (Ref. 29-33)

Clinical condition

• Decreased mental status• Focal neurological deficits• Cranial nerve palsies• Convulsions• Mechanical ventilation

Coexisting miliary or extrameningealtuberculosis/ coinfection with HIV

Age• Very young• Age greater than 60 years

CSF values• Culture positive for MTB• Raised protein• Reduced glucose

Delayed or interrupted treatment

102 . Infectious Diseases Journal of Pakistan

in tuberculous meningitis are other bacterial meningitides,fungal infections, central nervous system toxoplasmosis andcentral nervous system lymphoma. The differential diagnosisof tuberculoma should include sarcoid granuloma, primarybrain tumors, pyogenic abscess, fungal infections, cysticastrocytoma, lymphoma, cysticercosis and metastatic lesions.The differential diagnosis in AIDS patients must includeopportunist ic infections such as toxoplasmosis.

Laboratory Methods

Conventional bacteriological methods rarely detectMycobacterium tuberculosis in cerebrospinal fluid (CSF) andare of limited use in the diagnosis of TBM. CSF protein between100-200 mg/dl, CSF glucose less than 40 mg/dl, CSF leukocytecount between 50-500/microl with predominant CSFlymphocytes are considered characteristic findings in TBMpatients

13. Tuberculous meningitis could be confirmed in half

of clinically suspected cases by this method.

Polymerase Chain Reaction (PCR) offers a rapid andfairly accurate diagnosis of tuberculous meningitis

14,15. Although

specificity and sensitivity as high as 100% have been reported,until there is advancement in PCR technique, this test alone isinsufficient as a single diagnostic test for tuberculosis

16,17.

Furthermore, in recent studies, immunological diagnostictechniques were found to be superior to PCR. These methods,owing to their rapid yield and easier method,also seem convenientfor use in laboratories in the developing world

18. Gene probes,

gene amplification methods and in situ approaches offerunparalleled capability to enhance the diagnosis of tuberculosisin the near future

19.

Radiological Evaluation

Modern imaging is a cornerstone in the early diagnosisof central nervous system tuberculosis and may preventunnecessary morbidity and mortality.

Chest X-ray:

The chest x-ray in patients with central nervous systemtuberculosis may show features of miliary or pulmonarytuberculosis. In about 47% of central nervous system tuberculosispatients, the CXR may not reveal any abnormalities

20.

Computerized Tomography (CT):

In patients with tuberculous meningitis, hydrocephalusis the most common (80%) abnormality detected by CT. Lesscommonly; parenchymal/basal cistern enhancement is noted.Cerebral infarcts and surrounding edema can be detected inapproximately 13% of patients, while tuberculomas can bedetected in up to 5% of patients with tuberculous meningitis.The CT can be normal in up to 12% of patients

20.

In patients with tuberculomas, the characteristic CTfinding is a nodular enhancing lesion with a central hypodenseregion. Such a lesion arising due to tuberculous involvementof the central nervous system is difficult to differentiate on CTfrom other intracranial diseases i.e. abscesses, neoplasms,multiple sclerosis, gliosis etc.

21. Extensive surrounding edema

and mass effects are usually seen in the acute inflammatorystage but are not as prominent in chronic tuberculomas

20. The

appearance of TBA on CT is similar tuberculomas and to thatof other intracranial abscesses, showing lesions with centralhypodensity and peripheral enhancement.

Magnetic Resonance Imaging (MRI):

Contrast enhanced MRI is generally considered as themodality of choice for detecting and assessing central nervoussystem involvement by tuberculosis. The MRI may demonstratelocalized lesions and meningeal enhancement

22,23. It is useful

for assessment of the location of lesions and their margins, aswell as ventriculitis, meningitis and spinal involvement(sensitivity 86%, specificity 90%). Choroid plexus enhancementwith ventricular enlargement on MRI is highly suggestive ofTBM. In TBM, MRI shows diffuse, thick, meningealenhancement. Cerebral infarcts can be seen in nearly 30% ofcases

24. While current radiological methods such as CT and

MRI are able to identify abnormalities highly suggestive andin some cases diagnostic of TBM, their overall diagnostic yieldis less than optimal.

The MRI features of the individual tuberculoma dependon whether the granuloma is non-caseating, caseating with asolid center, or caseating with a liquid center. The non-caseatinggranuloma usually is hypointense relative to brain on T1-Wimages and hyperintense on T2-Weighted (T2-W) images and,shows homogenous post-contrast enhancement. The caseatinggranuloma with solid caseation appears relatively hypointenseor isointense on T1-W images and isointense to hypointenseon T2-W images. The granulomas with central liquefaction ofthe caseous material appear centrally hypointense on T1-Wimage and hyperintense on T2-W images with a peripheralhypointense rim on T2-W images. Gadolinium enhanced T1-W images show rim enhancement in caseating granulomas.

Role of Biopsy

Establishing a diagnosis of TBT can be verychallenging as the TBT lesions are similar to myriad of otherlesions on imaging studies. Accurate diagnosis of tuberculomais not possible until the brain lesion in question is subjected tohistopathological examination. Seven out of 13 patients, whounderwent biopsy at AKUH for suspicion of tuberculoma, hadother diagnoses (unpublished observations). Although surgicalintervention is considered mandatory in clinically diagnosedtuberculoma patients with worsening clinical or radiologicalfeatures, definite guidelines regarding surgical biopsy fordiagnosis are lacking.

Oct - Dec 2004 . 103

Treatment and Prognosis

Anti-tubercular therapy (ATT) is the mainstay ofmanagement in central nervous system tuberculosis. Meta-analysis and RCT have suggested that corticosteroids arebeneficial in the survival of patients with CNS TB

25,26. The

duration of ATT may need to be adjusted to radiological responsewhen treating tuberculomas

27. Despite ATT, mortality is reported

to be high in tubercular abscesses9.

Surgery has a role both in the diagnosis and treatmentof tuberculoma. It is usually indicated in cases of clinicaldeterioration that fail to respond to medical management andwhen the diagnosis of tuberculoma is in doubt. Surgicaltreatment options for TBA include simple puncture, continuousdrainage, fractional drainage, repeated aspiration through a burrhole, stereotactic aspiration and total excision of the abscess.Ventriculoperitoneal shunts may be required in patients withTBM or TBT who develop obstructive hydrocephalus.Ventriculoperitoneal shunt should be performed at the time theneed for shunting is determined and should not be delayedwaiting for the infection to resolve

28.

Despite prompt initiation of effective ATT, centralnervous system tuberculosis continues to have a poor prognosis.Complications of tuberculous meningitis constitute the majorcauses of morbidity and mortality of central nervous systemtuberculosis, especially in the pediatric population.

Patients with stage 1 disease at presentation usuallymake a complete recovery or are left with only mild neurologicaldeficits, while around 30% of patients with advanced stage atpresentation succumb to severe residual neurological sequelae

29.

Those who survive central nervous system tuberculosis are leftwith serious dysfunctions such as cognitive disturbances,seizures, hemiparesis, ataxia, visual impairment, optic atrophyand other persistent cranial nerve palsies. Children and olderpersons, because of their less competent immune systems aremore vulnerable to contracting central nervous systemtuberculosis. In a recent study, approximately 28% of paediatricpatients with central nervous system tuberculosis died and 40%were left with permanent severe neurological sequelae

30. Some

of the predictors of poor prognosis in patients with centralnervous system tuberculosis are shown in table 3. It is likelythat BCG protects against a fatal outcome in tuberculousmeningitis

36.

Conclusion

Central nervous system tuberculosis is one of the moresevere forms of extra-pulmonary tuberculosis. There has beena significant increase in the incidence of CNS TB worldwideover the last couple of decades.

It may present as tuberculous meningitis, tuberculoma,tuberculous abscess, or encephalopathy. Its diagnosis relies on

laboratory studies of the CSF and/or visualization of a lesionon CT or MRI. Newer diagnostic techniques, such as PCR,have not been assessed completely and are not possible in mostsettings in the developing world. Neurosurgeons have beenactively involved in the treatment of central nervous systemtuberculosis due to its propensity to cause obstructivehydrocephalus, intracranial mass lesions, and compressivemyelopathy. Surgery has a role both in the diagnosis and/ortreatment of tuberculoma and tubercular brain abscess althoughdefinite guidelines have yet to be formulated. A high indexof suspicion is required in order to avoid delays in diagnosis,which may influence treatment outcome. Death may occur asa result of missed diagnosis and delayed treatment.

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17. Katoch VM. Newer diagnostic techniques for tuberculosis. Indian J Med Res. 2004 Oct;120(4):41828

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Volume 3 Number 1.

36. Jamison DT, Creese A, Prentice T: World Health

Report 1999. World Health Organization.

104 . Infectious Diseases Journal of Pakistan

PERSPECTIVES

SUMO Vs VirusesWhat’s the Connection?

Romena Qazi

Department of Pathology and Microbiology,

The Aga Khan University, Karachi, Pakistan.

Corresponding Author: Romena QaziAssistant Prof., Dept. of Pathology and MicrobiologyThe Aga Khan University, Karachi, PakistanE.mail: romena.qazi@aku.edu

Some proteins are synthesized inactive and need to be post-

translationally modified to become active. These various types

of modifications are phosphorylation (addition of PO4),

acetylation (CH3CO), methylation (CH3), and ubiquitination

(Ub). One type of modification that has been receiving a lot of

attention lately is the addition of a 97 AA peptide, called SUMO

(for small ubiquitin-like modifier), to a number of proteins.

It is well known that proteins that are targeted for

degradation are modified by ubiquitin, a 76 amino acid peptide.

This is carried out by the E1, E2 and E3 ubiquitin activating,

conjugating and ligating enzymes, respectively. Although there

is only one type of E1, four different types of E2 and over 100

different types of E3 are found in humans; overall there are

over 300 different combinations of the E2-E3 enzymes each of

which specifically target different sets of proteins. Once modified,

the mono or poly-ubiquitinated proteins are subsequently

degraded by the 26S proteosome, which represents 1% of the

total protein inside a eukaryotic cell, into small peptides. Thus

ubiquitination is an irreversible modification (no de-ubiquitinases

have been found!) whose primary function is to degrade proteins.

Like ubiquitin, SUMO modification also takes place

on the terminal amino group of lysines. Moreover, there are

E1, E2 and E3 SUMO ligases whose respective functions mirror

that of the ubiquitin modifying enzymes. SUMOylation is a

reversible process that is catalyzed by de-conjugation proteases

Ulp/Senp. Other homologs of SUMO, namely SUMO-2 and

SUMO-3 have also been found recently and even though

SUMO2 and SUMO3 share 50% amino acid sequence identity

with SUMO1, both are functionally different.

The main difference between the two is that

SUMOylation can modify the function, activity, or localization

of its various target proteins. Although the biological roles of

SUMO modification remain poorly understood, recent reports

suggest that SUMOylation plays an important role in protein

stability, DNA repair, gene regulation, protein transport, and

chromosomal segregation. Additionally, SUMOylation has been

shown to play an active role in neurodegenerative diseases such

as Huntington’s and Alzheimers. For instance, it has been shown

recently that the Huntingtin protein (Htt) becomes more

neurotoxic after it has been SUMOylated.

A number of recent reports have also demonstrated

that SUMOylation can enhance the infectivity by certain viruses.

Human cytomegalovirus (HCMV) is a member of the herpesvirus

family and while HCMV poses a low threat to healthy

individuals, it is life threatening to the immuno-compromised

patients. HCMV infection requires the expression of IE1 (72

kDa) protein. Interestingly, SUMO1 modification of IE1

increases HCMV replication by promoting accumulation of

IE2 (86 kDa) protein. Inhibition of sumoylation therefore would

prevent infection by HCMV. This demonstrates that SUMO

might be a good target for therapeutic intervention against

HCMV infection.

New therapies are eagerly sought after to find the

possible treatment of HIV. HIV-1 expresses several regulatory

proteins that divert key cellular factors to allow rapid and

efficient production of viral particles. Research for small peptides

to penetrate and bind to the target protein has found two

regulatory proteins; Tat and Rev. Tat and Rev are small proteins

that act through protein-protein interactions, which is absolutely

necessary to viral replication. Both Tat and Rev are stabilized

by SUMO-1 modification which led to the formation of small

protein ,SUMO-1 heptapeptide transduction domain SHP, that

can efficiently penetrate within primary lymphocytes and inhibit

the function of Rev. These proteins have also been shown to

inhibit viral replication in both lymphocytes and macrophages.

Thus sumoylated small proteins might represent new therapeutic

agents useful for impairing generation of new viral particles.

Other targets of SUMO addition include DNA repair

and genome stability proteins, stress related proteins, DAXX,

and transcription factors. The transcriptional activation of p53,

called the “guardian of the genome” is increased by SUMO

addition. Sumoylation may also alter the stability of proteins

with polyglutamine repeats involved in neurodegenerative

disorders, adding further and diverse roles of this modification

system.

Oct - Dec 2004 . 105

20 year old young man presented to a general physicianwith complaints of high grade fever (103-104

0F) for last five

days with right sided abdominal pain without any nausea,vomiting or cough. On examination he was unable to take adeep breath because of pain, there was no positive finding onthe rest of the abdominal exam.

What should be the next step?

Ultrasound abdomenBroad spectrum antibioticsCXRAbdominal X RayUrine D/R.

Although the patient had symptoms suggestive ofintrabdominal pathology we have to remember that causesabove the diaphragm can also lead to abdominal pain. Thispatient had abdominal ultrasound performed which demonstratedmoderate right sided pleural effusion and the rest of the examwas normal.

At this stage what should be the next most appropriatestep.

Diagnostic PleurocentesisTherapeutic pleurocentesisAntibiotics to cover for community acquired pneumoniaCBC and ESRPleural biopsy

Patient was started on broad spectrum antibiotics afterCBC and diagnostic pleurocentesis performed as an out patient.He was also started on adequate analgesia to control the pleuritcchest pain

The results of CBC demonstrated :

Hemoglobin 14Gm/LTlC 6500mm

3

Neutro 47%Lympho 48%Platelets normal

The pleural fluid analysis demonstrated :

Protein 5 Gm/L

LDH 450 IU

Pleural fluid cell count

neutrophils 47%

lymphocytes 46%

many mestohelial cell

At follow up visit after two days; he was still febrile

but feeling a little better with adequate pain relief.

At this point in the course of his illness what is the

most appropriate next step.

Hospitalize the patient and start I/v antibiotics

Change the antibiotics and continue out patient

treatment

Repeat the pleurocentesis to rule out complicated para

pneumonic effusion /empyema

Pleural biopsy to rule out acute tuberculous pleuritis

Continue with present antibiotic as it is too early to

see the response.

At this stage of patient’s illness, although with exudative

effusion and high grade fever, acute community acquired

pneumonia with parapneuomonic effusion is the most plausible

diagnosis but a few things are atypical for this presentation.

He presented with symptoms suggestive of pleuritis

without any cough, sputum production antecedent to the pain.

With high grade fever and moderate exudative effusion his

TLC count is not elevated also the chest X-ray does not

demonstrate any underlying consolidation so alternate diagnosis

must be considered, including acute tuberculous pleuritis.

Patient underwent pleural biopsy while initial antibiotics

were continued.

Pleural biopsy demonstrated caseous necrosis. AFB

smear was negative and PCR for mycobacterium Tuberculosis

was positive. Diagnosis of acute tuberculous pleuritis was made

and he was started on standard four drug anti-tuberculous

treatment.

Discussion:

Diagnosis of tuberculous pleuritis should be kept in

mind in any patient with an exudative pleural effusion. When

a tuberculous effusion results in the absence of radiologically

apparent tuberculosis it may be the continuation of primary

infection 6 to 12 weeks formerly or it may represent reactivation

tuberculosis. The tuberculous pleural effusion is believed to

CASE REPORT

A Young Man with Fever and Abdominal Pain.

Jawed Abubaker, Mariam Akram,

Department of Medicine, Liaquat National Hospital, Karachi.

Corresponding Author:Jawed Abubaker, Mariam Akram,

Department of Medicine, Liaquat National Hospital, Karachi.

106 . Infectious Diseases Journal of Pakistan

result from disruption of sub pleural caseous foci into the pleural

space. It leads to the entry of the tuberculous proteins in to the

pleural space generating a hypersensitivity reaction.

Although tuberculous pleuritis and pleural effusion are generally

considered a chronic illness; tuberculous pleuritis is usually an

acute febrile illness causing a nonproductive cough and pleuritic

chest pain mimicking acute bacterial pneumonia, but without

an elevation in the peripheral white blood cell (WBC) count.

If both cough and chest pains are present, pain usually antedates

the cough1. Night sweats, chills, weakness, dyspnea, and weight

loss can also occur. In one series one quarter of the patients

had initial symptoms of less than a week in duration, where as

almost three quarter had symptoms for almost a month2 .

Sometimes the onset is less acute with only mild chest pain,

perhaps with non productive cough, a low grade fever, easy

fatigability and weight loss 1. Pleural effusion due to tuberculous

pleuritis is usually unilateral and can be of any size. In about

20% of patients with tuberculous effusion parenchymal diseases

is radiologically visible almost always on the same side of the

effusion and invariably represents an active parenchymal

disease3.

Diagnosis:

The identification of tuberculous pleural effusion

depends upon the display of tubercle bacilli in the sputum,

pleural fluid, or pleural biopsy specimen, or the expression of

granulomas in the pleura. The primary diagnostic tests in

tuberculous pleuritis involve sampling of the pleural fluid and

pleural tissue. Pleural fluid mycobacterial smears are generally

negative, unless the patient has tuberculous empyema. Pleural

fluid culture is positive for M. tuberculosis in fewer than 40

percent of patients; a BACTEC system with bedside inoculation

provides a higher yield than do conventional methods. Pleural

biopsy culture is positive in 64 percent4. Pleural tissue can be

obtained via thoracoscopy or closed percutaneous needle biopsy.

The two methods are believed to have comparable sensitivities,

and the latter is generally preferred because it does not require

general anesthesia. Sputum culture is less sensitive. It is positive

in 20 to 50 percent of cases, being much more likely to occur

in patients with parenchymal disease.

On histological examination, the presence of pleural

granulomas is virtually diagnostic of tuberculosis. Caseation

and demonstration of acid-fast bacilli are not required, although

noncaseating pleural granulomas can occasionally be seen in

other disorders such as, fungal disease, tularemia, sarcoidosis

and rheumatoid lung disease. The initial pleural biopsy in

tuberculous pleuritis is positive in approximately 70 percent of

cases5. A greater number of biopsies taken at a single session

(6 or more), or multiple, separate biopsy procedures can increase

the sensitivity to 80 percent6. However, multiple biopsy sessions

are usually not necessary because the combination of histological

examination and culture of the initial pleural biopsy is over 90

percent sensitive. This combination is regarded as the most

sensitive diagnostic test for pleural tuberculosis.

Pleural fluid analysis:

Characteristics of the pleural fluid – The effusion

in tuberculous pleuritis is straw-colored in more than 80 percent

of cases. It has the following characteristics:

The fluid is invariably an exudate. The protein

concentration is usually above 3.0 g/dL, and is greater

than 5.0 g/dl in 50 to 77 percent of cases.

The pleural fluid LDH level is usually elevated

A low pH and glucose concentration can occur. The

pleural fluid glucose concentration in tuberculous

pleurisy is usually between 60 and 100 mg/dL, with

levels below 50 mg/dL being found in only seven to

twenty percent of effusions.

Extremely low levels can occur (<30 mg/dL), but are

rare and usually associated with tuberculous empyema. The

pleural fluid pH is virtually always less than 7.40, with 20

percent of patients having a pH below 7.30.

The nucleated cell count in the effusion is usually

between 1000 and 6000/mm3. It is lymphocyte predominant

in 60 to 90 percent of cases; the remaining patients have

neutrophil predominance, in which the neutrophils occasionally

account for more than 90 percent of the cells. Lymphocytes

predominate in subacute and chronic tuberculous effusions. In

patients with symptoms of less than two weeks duration,

neutrophils predominate, an observation which is in accord

with the findings in experimental pleurisy. The time course for

the transition from neutrophils to lymphocytes in humans is

unknown, if serial thoracenteses are performed, the differential

count reveals a change to predominantly small lymphocytes1,2

.

The pleural fluid in TB pleuritis rarely contains more

than five percent mesothelial cells7-10

. Lack of mesothelial cells

is also not diagnostic for TB as any condition in which the

pleural surface is extensively involved will lead to absence of

mesothelial cell. Prominent eosinophil infiltration is also

uncommon. The presence of more than 10 percent eosinophils

usually excludes the diagnosis of tuberculous pleuritis unless

the patient has had a previous pneumothorax or thoracentesis

(Previous thoracentesis and or pneumothorax can introduce air

and or blood which leads to the pleural fluid eosinophilia).

Tuberculin skin testing – A negative skin test does

not rule out the diagnosis of tuberculous pleuritis as in about

30% of patient tuberculin skin testing will be negative3. If the

patient is retested in about 2 months after the onset of symptoms,

the skin test is invariably positive.

Oct - Dec 2004 . 107

One possible explanation for the initial negative skin

test is the suppression of sensitized T-cells in the peripheral

circulation and skin by circulating adherent mononuclear cells

(chiefly monocytes, not classic CD8 suppressor cells). These

monocytes are known to suppress antigen-induced lymphocyte

blastogenesis and the production of interleukin-2.Second, there

may be sequestration of reactive T lymphocytes in the pleural

space11,12

.

Although in countries where tuberculous disease is

uncommon, the positive tuberculin skin test will be a valuable

information in narrowing down the differential diagnosis. In

countries like Pakistan where mycobacterial disease is endemic,

the tuberculin skin testing should not be used as a diagnostic

tool for tuberculosis.

Special tests – Several special tests, such as pleural

fluid adenosine deaminase and lysozyme concentrations, have

been investigated for use in diagnosing tuberculous pleural

effusions. None are routinely used at present.

Adenosine deaminase – Pleural fluid adenosine

deaminase (ADA) concentrations are elevated in tuberculous

pleural effusions. Some large series suggest that ADA is 100

percent sensitive and 95 to 97 percent specific when a value

above 45 to 60 U/L is found13

. In a 1999 analysis of 216 patients

with pleural effusion, a receiver operating characteristic curve

identified the best cutoff at 60 U/L, yielding an excellent

sensitivity (0.95), specificity (0.96), positive predictive value

(0.96), and negative predictive value (0.95)14

. Specificity is

decreased by high ADA levels that occasionally occur in other

conditions such as rheumatoid effusion, empyema, mesothelioma,

lung cancer, parapneumonic effusion, and hematologic

malignancies15

. Choosing a lower ADA cutoff valve will increase

sensitivity at the expense of specificity14,16

.

These variable findings may reflect in part failure to

distinguish between the two principal isoenzymes, ADA-1 and

ADA-2. ADA-2 is increased in tuberculous effusions, while

ADA-1 rises in empyemas17

. Most studies have reported only

the total ADA level13,16,17.

At present, pleural fluid ADA remains "an aid to

differential diagnosis," as it was originally described in 197813

.

It is most useful in the 10 percent of patients with tuberculous

pleurisy who have negative standard diagnostic studies, i.e.,

negative pleural histology and culture18-19

.

Lysozyme – Pleural fluid lysozyme concentrations

are greater than 15 mg/dL in over 80 percent of tuberculous

pleural effusions16

. However, the highest concentrations are

found in empyemas. Another limitation to this test is the overlap

between tuberculous and malignant effusions.

The pleural fluid-to-serum lysozyme ratio may be

more useful than the absolute value. If empyemas are excluded,

a ratio above 1.2 has been reported to have 100 percent sensitivity

for tuberculous effusions and 95 percent specificity20

.

Gamma interferon – Measurement of pleural fluid

gamma interferon also may be useful. A gamma interferon

concentration above 140 pg/mL had a sensitivity of 94 percent

and a specificity of 92 percent for detecting tuberculous effusions

when tested in 145 patients21

. A second study in 66 patients

with exudative, lymphocytic pleural effusions found a sensitivity

of 95 percent and a specificity of 96 percent for the test when

a cut-off value of 240 pg/mL was employed2 2 , 2 3

.

Polymerase chain reaction – Polymerase chain

reaction has a sensitivity of only 42 to 81 percent24,25

and is

expensive. Its use in this setting is not currently recommended.

In establishing the diagnosis of TB-pleuritis, it was not found

superior either to pleural fluid ADA or interferon gamma levels25

.

Natural history:

In most patients the pleural effusion will subside

without treatment within 2-4 months; only to return as active

tuberculosis at a later date in about 43-65%26-27

.There are no

predicting features including the size of the initial effusion or

the presence or absence of parenchymal disease on a CXR.

Recommendation:

Tuberculous pleural effusion is third most common

presentation of tuberculous disease after pulmonary and lymph

node involvement. Pakistan ranked 8th among countries with

the highest disease burden. Any exudate pleural effusion either

acute or chronic especially with lymphocytosis (neutrophil:

lymphocyte> 0.75) should be treated as tuberculosis until proven

otherwise. At present special tests for the diagnosis of tuberculous

pleuritis are not available in Pakistan. Pleural biopsy should be

performed and only if either AFB smear or the culture is positive

or the biopsy demonstrates granulomas the treatment of

tuberculosis should be started.

Pearls:

Extra-abdominal causes can lead to significant

abdominal pain.

All acute exudate effusion are not parapneumonic

Pleural fluid neutrophilia does not rule out tuberculous

pleuritis

Pleural fluid lymphocytosis is not pathognomonic for

tuberculous pleuritis

Pleural biopsy is diagnostic in acute tuberculous

effusion

108 . Infectious Diseases Journal of Pakistan

References

1. Berger. HW, Mejia E. Tuberculous pleurisy.Chest

1973;63:88-92

2. Levine H, Szanto PB, Cugell DW. Tuberculous

pleurisy: an acute illness. Arch Intern Med 1968;

122:329-332

3. Valdes L, Alvarez D, San Jose E, et al. Tuberculous

pleurisy. A study of 254 patients. Arch Intern Med

1998;158;2017-2021

4. Levine H, Metzger W, Lacera D, Kay L. Diagnosis of

tuberculous pleurisy by culture of pleural biopsy

specimen. Arch Intern Med 1970;126:269-272

5. Emad A, Rezaian GR. Diagnostic value of closed

percutaneous pleural biopsy versus pleuroscopy in

suspected malignant effusion or tuberculous pleurisy

in a region with a high incidence of tuberculosis: a

comparative age-dependent study. Respir Med

1998;92:488-500

6. Kirsch CM, Kroe M, Azzi R, et al. The optimal number

of pleural biopsy specimens for a diagnosis of

tuberculous pleurisy. Chest 1997;112:702-706

7. Yam LT. Diagnostic significance of lymphocytes in

pleural effusions. Ann Intern Med 1967;66:972-982

8. Light RW, Erozan YS, Ball WC. Cells in pleural fluid:

their value in differential diagnosis. Arch Intern Med

1973;132:854-860

9. Sapriggs AI, Boddington MM. The cytology of

effusions, 2nd ed. New York: Grune & Stratton,1968.

10. Hurwitz S, Leiman G, Shapiro C. Mesothelial cells in

pleural fluid: TB or not TB? S Afr Med J 1980;57:937-

939

11. Ellen JJ. Pleural fluid and peripheral blood lymphocyte

function in tuberculosis. Ann Intern Med 1978;89:932-

933

12. Rossi GA, Balbi B, Manca F. Tuberculous pleural

effusions: evidence for selective presence of PPD-

specific T-lymphocytes at site of inflammation in the

early phase of the infection. Am Rev Respir Dis 1987;136:575-579

13. Piras MA, Sakis C, Brudoni M, Andreoni G. Adenosinedeaminase activity in pleural effusions: An aid to differential diagnosis. Br Med J 1978;2:1751-1759

14. Riantawan P, Chaowalit P, Wongsangiem M, Rojanaraweewong P. Diagnostic value of pleural fluid

adenosine deaminase in tuberculous pleuritis with

reference to HIV coinfection and a Bayesian analysis.

Chest 1999;116:97-107

15. Ocana I, Martinez-Vazquez JM, Segura RM, et al.

Adenosine deaminase in pleural fluids: Test for

diagnosis of tuberculous pleural effusion . chest

1983;84:51-59

16. Valdes L, San Jose E, Alvarez D, et al. Diagnosis of

tuberculous pleurisy using the biological parameters

adenosine deaminase, iysozyme and interferon

gamma. Chest 1993;103:458-463

17. Burgess LJ, Maritz FJ, Le Roux I, et al. Use of

adenosine deaminase as a diagnostic tool for

tuberculous pleurisy. Thorax 1995;50:672-674

18. Orriols R, Coloma R, Ferrer J, et al. Adenosine

deaminase in tuberculous pleural effusion. Chest

1994;106:1633-1638

19. Gakis C. Adenosine deaminase in pleural effusions.

Chest 1995;107:1773-1779

20. Verea Hernando HR, Masa Jimenez JF, Dominguez

Juncal L, et al. Meaning and diagnostic value of

determining the lysozyme level of pleural fluid. Chest

1987;91:342-351

21. Wongtim S, Silachamroon U, Ruxrungtham K, et al.

Interferon gamma for diagnosing tuberculous pleural

effusions. Thorax 1999;54:921-931

22. Ribera E, Ocana I, Martinez-Vazquez JM, et al. High

level of interferon gamma in tuberculous pleural

effusion. Chest 1988;93:308-311

23. Villena V, Lopez-Encuentra A, Echave-Sustaeta J, et

al. Interferon-gamma in 388 immunocompromised

and immunocompetent patients for diagnosing pleural

tuberculosis.Eur Respir J 1996;9:2635-2639

24. Villena V, Rebello MJ, Aguado JM, et al. Polymerase

chain reaction for the diagnosis of pleural tuberculosis

in immunocompromised and immunocompetent

patients. Clin Infect Dis 1998;26:212-214

25. Querol JM, Minguez J, Garcia-Sanchez E, et al. Rapid

diagnosis of pleural tuberculosis by polymerase chain

reaction. Am J Respir Crit Care Med 1995;152: 1977-

1981

26. Patiala J. Initial tuberculous pleuritis in the Finnish

Armed Forces in 1939-1945 with special reference

to eventual post pleuritic tuberculosis. Acta Tuberc

Scand 1954;36{Suppl}:157

27. Roper WQH, Waring JJ. Primary serofibrinous pleural

effusion in military personnel. Am Rev Respir Dis

1955;71:616-634

Oct - Dec 2004 . 109

CASE REPORT

Bacteremia Associated with Central Line Infection by Chryseomonas Luteola in a Case of RecurrentMeningiomas.

Muhammad Nasim Sabir*, Bushra Jamil*, Sajjad Ahmed**

Departments of Medicine, Pathology, Microbiology* and Neurology,

The Aga Khan University Hospital, Karachi, Pakistan.

Case Summary

A 52 years old diabetic and asthmatic lady was admitted

in the Neurosurgery service with a post-operative wound

infection 10 days following removal of meningioma. The patient

had a history of recurrent meningiomas for which she had

undergone multiple surgeries during the past ten years.

On admission, the patient was febrile and drowsy.

There surgical wound site over the scalp was swollen, exuding

a pussy discharge. Subsequently, a lumbar drain was inserted

for CSF drainage, the yellowish discharge from the wound was

sent for culture, which grew Streptococcus pyogenes for which

I/V Ceftriaxone was started. The patient improved and remained

stable till about the 25th day of hospital stay when she developed

fever, chest infiltrates as well as copious pussy discharge from

the wound.

Due to rapid deterioration in patient’s condition she

was shifted to ICU. Piperacillin tazobactam was started and

lumbar drain was removed. The scalp wound was re-explored

and a flap closure was done; an epidural drain was inserted for

CSF drainage. As the patient did not improve clinically, all

antibiotics were stopped and patient was rescreened for infection.

One set of blood culture drown from a peripheral vein and the

tip of pulmonary artery catheter grew Chryseomonas luteola.

This organism was sensitive only to Ofloxacin and the patient’s

antibiotic regimen was changed to Ofloxacin along with

Aztreonam and Amikacin. The patient gradually improved on

this regimen, was moved out of the ICU and subsequently

managed in the ward.

Discussion

Chryseomonas (CD4 group Ve-1) are normal inhabitant

of soil and environment usually regarded as a saprophyte or

commensal rarely recorded as pathogenic to humans1-3

.

Previously they were named as Pseudomonas luteola due to

resemblance with Pseudomonas. Most victims are

immunocompromised or immunocompetent patients with a

foreign body inserted.

Chryseomonas luteola is a non-sporing non-motile

gram negative rod with a distinct yellow orange pigment. Growth

on Mackonkeys agar shows rough or wrinkled colonies,

biochemically they are non lactose fermenters, oxidase negative

and catalase positive. Chryseomonas luteola has been reported

to cause septicemia4, bacteremia in cases of granulomatous

hepatitis 5, prosthetic valve endocarditis

6, meningitis associated

with intracranial prosthesis 7 and in patients with indwelling

intra-vascular catheters8. Bacteremia with Chryseomonas luteola

has been noted in immunocompromised patients, especially

those with an indwelling catheters.

Few clinical case reports have been published regarding

isolation of Chryseomonas luteola. In one such published report

by Ghosh 3 this organism was isolated from a superficial

cutaneous infection on face in an AIDS patient. Another report

of Chryseomonas related facial cellulites was reported by

Rastogi et al9 in a homosexual HIV-negative male.

Rahav et al10

in his case series reported four cases of

Chryseomonas luteola, in which two of the cases were associated

with the presence of a central line; one strain was isolated from

an infected hip joint and another one from ascitic fluid of a

patient with colonic carcinoma.

Most clinical isolates of Chryseomonas luteola reported

so far have been resistant to ampicillin, tetracyclines,

trimethoprim–sulfamethoxazole and first and second generation

cephalosporins, but susceptible to third generation

cephalosporins, mezlocillin, imipenam, aminoglycosides and

quinolones11-13

.

In the present case, though the patient was not labeled

as immunocompromised but history of steroid therapy in past

and multiple surgeries for recurrent meningiomas, with prolonged

hospital stay make her immune status compromised.

In the present case, the patient was not a labeled as

immunocompromised and was not on any regular

immunosuppressive therapy when she developed this infection.

Chryseomonas luteola was isolated both from the

pulmonary catheter tip and blood culture, suggesting bacteremia

secondary to line colonization. Like all previously reported

Chryseomonas luteola, our isolate was sensitive to

fluorouinolones and patient was treated with Ciprofloxacin and

recovered from the infectionCorresponding author: Muhammad Nasim Sabir, Departmentof and Neurology The Aga Khan University Karachi Pakistan

110 . Infectious Diseases Journal of Pakistan

Isolation of a rare organism like Chryseomonas luteola

underscores a need for clinicians as well as laboratories to be

aware of the importance of such organisms as pathogens,

particularly in critically ill or immunocompromised patients.

With increasing numbers of patients with immunodeficiencies

with long term indwelling catheters and prostheses, and

increasing use of immunosuppressive therapy for various

conditions, isolation of such organisms in clinical samples

should be evaluated critically and special care must be taken

before disregarding them as contaminants.

References

1. Moake JL. Hemolytic –uraemic syndrome: basic

science. Lancet 1994; 343:393-97.

2. Hawkins RE, Moriarty RA, Lewis DE, Oldfield EC.

Serious infections involving the CDC group Ve

bacteria Chryseomonas luteola and Flavimonas

oryzihabitans. Rev Infect Dis 1991; 13:257-60.

3. Ghosh SK. A rare infection caused by Chryseomonas

luteola. J Infect 2000; 41:109-10.

4. Neild GH. Hemolytic –uraemic syndrome in practice.

Lancet 1994; 343:398-401.

5. Rao TKS, Freidman EA, Nicastri AD. The types of

renal disease in the acquired immunodeficiency

syndrome. NEJM 1987; 316: 1062-68.

6. Rao TKS. Renal complications in HIV disease. Med

Clin North Am. 1996; 80: 1437-51.

7. Williams DI, Williams DJ, Williams IG, Unwin RJ,

Griffiths MH, Miller RF. Presentation. Pathology and

outcome of HIV associated renal diseases in a specialist

centre for HIV/AIDS. Sex Transm Inf 1998; 74: 17984.

8. Smith MC, Pawar R, Corey JT. Effect of corticosteroids

therapy on human immunodeficiency virus associated

nephropathy. Am J Med. 1994; 97:145-51.

9. Rastogi S, Sperber SJ. Facial cellulitis and

Pseudomonas luteola bacteremia in an otherwise

healthy patient. Diagn Microbiol Infect Dis 1998; 32:

303-5.

10. Rahav G, Simhon A, Mattan Y, Moses AE, Sacks T.

Infections with Chryseomonas luteola (CDC group

Ve-1) and Flavimonas oryzihabitans (CDC group Ve2).

Medicine (Baltimore) 1995; 74: 83-8.

11. Steinberg JP. Other gram negative bacteria in Mandell

GA, Bennett JE, Dolin R. editors. Principles and

practice of Infectious diseases 5th ed. Churchill

Livingstone Philadelphia 2000.

12. Kostman JR, Solomon F, Fekete T. Infections with

Chryseomonas luteola (CDC group Ve-1) and

Flavimonas oryzihabitans (CDC group Ve-2) in

neurosurgical patients. Rev Infect Dis 1991; 2: 2336.

13. Soloaga R, Procopio A, Manganello S, Ivanovic V,

Romay N, Pirosanto Y et al. Utility of prolonged

incubation and terminal subcultures of blood cultures

from immunocompromised patients. Rev Argent

Microbiol 2001; 33: 177-81

Oct - Dec 2004 . 111

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A 30 Year Old Asian Male with Right Sided Lower Abdominal Pain and Fever

Azizun-nisa Raza , Rashida Ahmed, Nausheen Yaqoob and Shahid Pervez

Department of Pathology & Microbiology, Aga Khan University, Karachi, Pakistan

A 30- year old Asian male presented with severe right-sided lower abdominal pain, fever, nausea and vomiting for the last 2 days.

He had no significant prior medical history. On physical examination, he had a temperature of 390C. The abdomen was soft with

normal bowel sounds; however, right iliac fossa was tender. The liver span was 15 cm at the right mid- clavicular line. The rest

of the findings from the physical examination were normal. Stool tested trace positive for occult heme.Levels of routine serum

electrolytes and of routine blood, tests of liver function were within normal limits. The hemoglobin was 12.6 gm/mL3 and the

leukocyte count was 19,600/ml with 57% neutrophils, 28% band forms and 4% eosinophils. Abdominal roentgenogram was

within normal limits. No appendicolith was present. A diagnosis of acute appendicitis was made. He underwent appendicectomy

and specimen was sent for histopathology. On gross inspection appendix appeared dilated and measured 5x1.5 cms. On sectioning

lumen was filled with necrotic material and mucosa was sloughed. Sections from the resection margin, middle part and base of

appendix were submitted. Microscopic examination revealed extensive surface ulceration with transmural severe acute and chronic

non-specific inflammation. A profound flask –shaped ulcer containing exudative necrotic material with fibrin was seen in which

numerous large, round to oval organisms were identified containing intracytoplasmic erythrocytes. Invasion of venules and

lymphatics by these organisms was also appreciated.

Corresponding author: Azizun-nisa Raza, Department ofPathology & Microbiology, Aga Khan University, Karachi,Pakistan.

Legends

1. H&E Stain X 40.Showing intravascular rounded organisms along with luminal necrosis.2. Periodic acid-Schiff stain X 40 outlines the organisms.

What is your diagnosis?

PHOTO QUIZ

(See answer on page 114)

112 . Infectious Diseases Journal of Pakistan

NEWS & VIEWS

September 25. A “Walk for Rabies awareness” wasorganized by the IDSP, PMA, CDGK and Helpline Forum.This walk was led by Mr. Niamatullah Khan, City Nazim,Karachi. It was important in highlighting the problems associatedwith stray dogs and dog bites – prevention and control inKarachi.

November 20, 2004. HIV –AIDS Conference.National AIDS Control Programme (NACP) and InfectiousDiseases Society of Pakistan (IDSP) organized a conference atPearl-Continental Hotel, Lahore. The Program summary andspeaker was as listed:

Welcome Note Asma Bokhari, Chairperson NACPEpidemiology of HIV in Pakistan Sharaf Ali ShahA case series of over 100 patients Naseem SalahuddinDiagnostic aspects Mteen IzharIntroduction to anti-retroviral drugs Ferheen Ali

Adverse effects and interactions of ARV Yasser HussainWhen to start therapy and how? Aslam KhanWhen to change therapy? Mahmud JavidSpecial issues in children Anita ZaidiOpportunistic infections - prevention and Rx Shaukat BangashPost-exposure prophylaxis Sobia QaziTuberculosis and HIV MansurJavaidClosing Address Faisal Sultan

December 21, 2004. Seminar on “Dog bite and Rabiesin Karachi: how should we solve the problem?” Organized by

IDSP and City District Government Karachi (CDGK)

Auditorium, Civic Center, Karachi. The program was as listedbelow. A short video film on Rabies was also shown

IDSP Activities - September to December 2004

Moderator: Dr. Nayyer ul Islam,

Asst. Prof. of Medicine,

Abbasi Shaheed Hospital

Stating the Problem of Rabies

in Karachi. Dr. Naseem Salahuddin,

Member, WHO Expert Panel Committee

Seeking Solutions

Thailand’s success story: what

can we learn? Dr. Altaf Ahmed,

Consultant Clinical Microbiologist,

Liaquat National Hospital

Providing Optimum Care at Low Cost Dr. Syed Ali

Sardar,

Clinical Fellow A & E,

Liaquat National Hospital

Counting Number of Dogs and Dog Bites Dr. Aamir Khan,

Assistant & Director R&D,

Johns Hopkins University, USA

Dog Population Control

How we can all work together. Dr. Naseem Salahuddin,

Suggestions invited

Concluding Remarks, Niamatullah Khan,

City Nazim, Karachi.

Oct - Dec 2004 . 113

PHOTO QUIZ

DiscussionEntameba histolytica is an enteric protozoan that infects 10% of the world’s population resulting in 100,000 deaths per year1.Although itsprevalence is highest in poor developing countries having the lowest level of sanitation, the convenience of modern travel , high rates ofemigration,and existence of high-risk groups in developing countries require physicians throughout the world be familiar with the diverseclinical syndromes resulting from Entameba histolytica infection2. Entameba histolytica infection presents mainly in 2 clinical forms asintestinal and extraintestinal disease3.Intestinal disease occurs in 4 major types including asymptomatic colonization (cyst passage),acuteamoebic colitis, fulminant colitis, and ameboma 4,5.Stricture formation, ulcerative post dysenteric colitis, intussusception, extra intestinaldissemination, massive hemorrhageand intestinal perforation are the main complications of intestinal amebiasis 6-7

E.histolytica cysts, whichhave a chitin wall and four nuclei, are the infectious form because they are resistant to gastric acid. Amebiasis begins as a primary infectionof the colon by ingestion of the encysted protozoan E.histolytica in contaminated food or water8.Excystation occurs in small bowel and theresultant trophozoites are carried down the small intestine to settle in the most static areas, typically the cecum and sometimes the appendix.When E.histolytica attach to the colonic epithelium, lyses colonic epithelial cells, and invade the bowel wall.

The infection is asymptomatic until the invasion occurs. Amebiasis most frequently involves the cecum and ascending colon, followedin order by the sigmoid, rectum, and appendix. In severe full-blown cases, however, the entire colon is involved. Amoebae can mimic theappearance of macrophages because of their comparable size and large number of vacuoles; the parasites, however, have a smaller nucleus,which contains a large karyosome. Amoebae invade the crypts of the colonic glands, burrow through the tunica propria, and are halted by themuscularis mucosae. There the amoebae fan out laterally to create a flask-shaped ulcer with a narrow neck and broad base. as the lesionprogresses, the overlying surface mucosa is deprived of its blood supply and sloughs. The earliest amebic lesions show neutrophilic infiltratesin the mucosa, which later develop into ulcers that contain few host inflammatory cells and areas of extensive liquegactive necrosis. The mucosabetween ulcers is often normal or mildly inflamed. Amebiasis spreads to other areas of body such as to liver, lungs and brain through amebicinvasion of venules or lymphatics.

Intestinal invasion typically produces acute attacks of diarrhoea with loose, mucoid, bloodstained stools (amebic dysentery), fever,headache and nausea. Abdominal discomfort can range from mild discomfort to the more common gripping pain.

The association of appendicitis and amebiasis is an exceptionally rare occurrence with a few case reports series in the literature9 .

Luminal obstruction is accepted universally as the prime cause of appendicitis, and the association of appendicitis andparasites raisesthe possibility of a causative relationship between E.histolytica and appendicitis. This pathogenic process can affect the appendix both primarilyand secondarily. Widespread caecal disease can lead to primary appendiceal involvement or generalized bowel congestion can contribute tosecondary appendiceal swelling. Patients who present with symptoms and signs localized to the right lower quadrant, particularly those withrecent travel to endemic areas, should have clinical tests for amebiasis, including a serologic test for ameba and examination of specimensfrom stool or from endoscopic biopsies. Timely appropriate therapy before the development of significant abdominal findings is typicallycurative.10

References

1- Reed SL: Amebiasis: An update. clin Infect Dis 14:385-393,19922- Aucott JN, RavdinJI: Amebiasisandpathogenic intestinal protozoa. Infect Dis Clin North Am 7:467-485,19933- Petri Jr WA, Clark CG, Diamond LS: Host Parasite relationships in amebiasis: conference report.J Infect Dis 169:483-484, 19944- Pehrson PO: Amebiasis in a non-endemic country. Epidemiology, presenting symptoms and diagnostic methods. Scand J Infect Dis

15:207-214, 19835- 5Adams EB, Macleod IN:Invasive amebiasis I..Amebic dysentry and its complications. Medicine 56:315-323, 19776- Nazir Z, MoazamF. Amebic liver abscess in children. Pediatr Infect Dis J 12:929-932, 19937- Eggleston FC, Handa AK, Verghese M: Amebic peritonitis secondary to amebic liver abscess. Surgery:46-48,19828- Reeder MM, Palmer PES. Infections and infestations. In:Margulis AR.Burhenne HJ.editors. Alimentary tract radiology. st.louis: CV

Mosby 1983.p16489- R. Ahmed, H. Shaikh, M. Siddiqui and M . Ahmed. Amoebic appendicitis- A rare entity J. Pak med Asoci:44:92-93,199410- Drugs for parasitic diseases. Med lett 28:9-18,1986

Answer to Photo quiz

Amoebic Appendicitis

114 . Infectious Diseases Journal of Pakistan

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