Variation in incidence of serious adverse events after onchocerciasis treatment with ivermectin in areas of Cameroon co-endemic for loiasis

Variation in incidence of serious adverse events after

onchocerciasis treatment with ivermectin in areas of Cameroon

co-endemic for loiasis

Nana A. Y. Twum-Danso and Stefanie E. O. Meredith

Mectizan Donation Program, Decatur GA, USA

Summary objective To determine the incidence of serious adverse events (SAEs) after mass treatment with

ivermectin in areas co-endemic for loiasis and onchocerciasis, and to identify potential risk factors

associated with the development of these SAEs, in particular encephalopathic SAEs.

methods We retrospectively analysed SAEs reported to have occurred between 1 December 1998 and

30 November 1999 in central-southern Cameroon by chart review, interview and examination of a

subset of patients.

results The overall incidence of SAEs for the three provinces studied was 6 per 100 000. However,

for Central Province alone the incidence of SAEs was 2.7 per 10 000 overall, and 1.9 per 10 000 for

encephalopathic SAEs associated with Loa loa microfilaremia (PLERM). The corresponding rates for the

most severely affected district within Central Province (Okola) were 10.5 per 10 000 and 9.2 per 10 000

respectively. Symptoms began within the first 24–48 h of ivermectin administration but there was a

delay of approximately 48–84 h in seeking help after the onset of symptoms. First-time exposure to

ivermectin was associated with development of PLERM.

conclusion In Cameroon, the incidence of SAEs following ivermectin administration in general, and

PLERM cases in particular, varies substantially by district within the areas co-endemic for loiasis and

onchocerciasis. More intense surveillance and monitoring in the first 2 days after mass distribution in

ivermectin-naıve populations would assist in early recognition, referral and management of these cases.

The increased reporting of SAEs from Okola is unexpected and warrants further investigation.

Research is urgently needed to find a reliable screening tool to exclude individuals (rather than

communities) at risk of PLERM from the mass treatment program.

keywords loiasis, onchocerciasis, ivermectin, Cameroon, adverse drug reaction reporting systems,

community health services

Introduction

Worldwide, more than 120 million people are estimated to

be at risk for infection with the filarial parasite Onchocerca

volvulus. Current estimates of infected people total

17.7 million, most of whom live in Africa. The infection is

associated with chronic ocular, dermal and lymphatic

damage. Long term pathology includes blindness, severe

itching, skin lesions, subcutaneous nodules and generalized

lymphadenopathy, which clearly has major implications on

the physical, psychological health and economic produc-

tivity of affected populations [Workneh et al. 1993; World

Health Organization (WHO) 1995; Oladepo et al. 1997].

The Onchocerciasis Control Programme (OCP) in West

Africa was established in 1974 with the goal of controlling

onchocerciasis as a public health problem and barrier to

socioeconomic development using a vector control strategy

(WHO 1987). Weekly aerial larviciding of infested rivers

proved successful in reducing transmission and possibly

eliminating the disease from affected communities

(Hougard et al. 2001). However, vector control strategies

are costly and the OCP did not include Liberia, Nigeria,

Central and East African countries, where the disease was

also highly endemic. Large-scale chemotherapy was not

possible initially because there was no safe drug available.

The registration of the anthelmintic drug Mectizan�

(ivermectin, Merck, Sharpe & Dohme), for the treatment

of onchocerciasis in 1987 heralded a breakthrough for

onchocerciasis control. Once clinical and community trials

established ivermectin to be safe and effective for mass

treatment of onchocerciasis (Awadzi et al. 1985; De Sole

et al. 1989), and Merck & Co, Inc. committed to provide

Tropical Medicine and International Health

volume 8 no 9 pp 820–831 september 2003

820 ª 2003 Blackwell Publishing Ltd

the drug free of charge for as long as it is needed for the

treatment of onchocerciasis, the whole picture changed. As

ivermectin is microfilaricidal, treatment must be adminis-

tered annually over the estimated reproductive life of the

adult female worm, which may be up to 14 years (WHO

1995). A new strategy involving large-scale mass treatment

of onchocerciasis endemic communities with Mectizan�,

the donated form of ivermectin, was developed. The

Mectizan� Donation Programme (MDP) and its advisory

body, the Mectizan� Expert Committee, were established

in 1988 to ensure that good medical practice and approved

prescribing procedures are adhered to in ivermectin mass

treatment programmes.

Mass treatment with ivermectin is recommended in areas

where onchocerciasis represents a major public health

problem (i.e. prevalence of at least 40%) on the basis of

cost effectiveness. As with all mass distribution of vaccines

and pharmaceutical agents, a passive surveillance system

for Serious Adverse Events (SAEs) attributable to iver-

mectin is required of all mass treatment programmes

receiving a donation of ivermectin.

By December 1998, approximately 76 million cumula-

tive doses of ivermectin had been administered in

onchocerciasis mass treatment programmes in Africa,

Latin America and Yemen. During the same time period

84 SAEs were reported to the MDP through the passive

surveillance system. This gave rise to a cumulative

incidence of approximately one SAE case per 1 million

treatments. However, more than 75% of these 84 cases

(n ¼ 65) were from one geographical area: the central-

southern region of Cameroon. In this region, approxi-

mately 60% (37 of 65) of the SAEs were cases of

neurologic impairment after ivermectin administration,

one-quarter of which were associated with high intensity

infection with Loa loa, another filarial parasite (MDP

unpublished data).

Loiasis is generally believed to be benign, causing

dermatitis, fatigue, temporary localized oedema and epi-

sodic sub-conjunctival migration of the adult worm (Wahl

& Georges 1995). L. loa infection has also occasionally

been associated with spontaneous cases of encephalopathy

in which the patients’ blood and cerebrospinal fluid (CSF)

were positive for L. loa microfilariae (Van Bogaert et al.

1955). A temporal association has also been made between

treatment with microfilaricidal agents such as ivermectin

and diethylcarbamazine and the development of an

encephalopathy similar to that seen in spontaneous cases

(Van Bogaert et al. 1955; Ducorps et al. 1995). This

clinical entity, Probable L. loa Encephalopathy temporally

Related to Mectizan� treatment (PLERM), was first

defined by an independent group of experts consulting for

the MDP in 1995, as follows:

• coma (without seizures, usually with fever) occurring in

a previously healthy person with no other underlying

cause for the coma;

• onset of progressive disturbances of the central nervous

system (CNS) within 5 days of treatment with ivermec-

tin, without remission; and

• post-treatment blood smear showing >10 000 L. loa

microfilariae per millilitre (mf/ml), and/or CSF testing

positive for L. loa microfilariae (Anonymous 1996).

In 1999 alone, several cases of encephalopathy following

ivermectin treatment were reported to the MDP by a single

mass treatment programme within 1 month, from an area

of the central-southern region of Cameroon known to be

co-endemic for onchocerciasis and loiasis (MDP unpub-

lished data). These cases occurred in the context of

expansion of an existing mass treatment programme into

communities where most inhabitants would be expected

to be naıve to ivermectin. No epidemics of encephalopathy

of viral or bacterial aetiology were known to be occurring

in the region during that time period. All of the cases

occurred in an area where prior epidemiologic surveys had

documented L. loa prevalences of up to 38% in the adult

population (Boussinesq & Gardon 1997).

Other than age, gender, and dose of ivermectin, most of

the data on individual and community risk factors for

development of SAEs and for poor clinical outcomes were

incomplete at the time of initiation of this study. As under-

reporting of SAEs is believed to be common, the true

number of SAEs that occurred during that time period was

also unknown. This paper reports a retrospective study

of the incidence of SAEs after treatment with ivermectin

in a geographical area co-endemic for onchocerciasis and

loiasis in Cameroon, analyses potential risk factors

associated with developing SAEs, and compares the

characteristics of patients who developed CNS disturb-

ances to those with non-CNS illnesses after ivermectin

treatment.

Study area

The Republic of Cameroon is located in Central Africa.

It has an estimated population of 14.4 million of which

62% live in the rural areas (WHO 1999). In the rural areas,

most people live in mud huts or other such modest

accommodations along unpaved roads, which may be

several kilometres away from the main paved roads in the

town where most health facilities are located. The central-

southern region of Cameroon, where this study was

conducted, is climatically equatorial rainforest. It lies

within an area that has an estimated onchocerciasis

prevalence of 40% or more, thus making it eligible for

Tropical Medicine and International Health volume 8 no 9 pp 820–831 september 2003

N. A. Y. Twum-Danso & S. E. O. Meredith Adverse events after ivermectin treatment

ª 2003 Blackwell Publishing Ltd 821

mass treatment with ivermectin, while also being a high

risk area for L. loa infection (Thomson et al. 2000).

The SAE cases occurred in the Central, Littoral and West

Provinces of the country. For retrieval and clarification

of SAE reports, field visits were made to district hospitals in

Okola, Obala, Sa’a and Ngog Mapubi in Central Province,

and Pouma and Edea in Littoral Province. Additional

records were retrieved in the capital city of Yaounde at the

clinics of physicians at the Central Hospital of Yaounde,

the offices of the National Onchocerciasis Task Force

(NOTF) in the Ministry of Public Health (MOPH), and the

headquarters of Non-Governmental Development Organ-

izations (NGDOs) participating in the NOTF. We also

visited patients and family members in the District of

Okola in Central Province for interviews.

Materials and methods

Study population

The study population was defined as the total number of

people treated with ivermectin under the auspices of

onchocerciasis mass treatment programmes in Central,

Littoral and West Provinces of Cameroon between

1 December 1998 and 30 November 1999. The inclusion

and exclusion criteria were those of the MDP, i.e. all

members of an affected community were eligible with the

exception of children weighing <15 kg or smaller than

90 cm, pregnant women, women breast-feeding infants

<1 week old, and persons with serious acute or chronic

illnesses (MDP 1998). The study was approved by the

Chairman of the NOTF of Cameroon and the institutional

review board of Emory University.

Case definition

A case was defined as an individual who developed an

SAE within 7 days of being administered ivermectin in an

onchocerciasis mass treatment programme, where the

onset of the SAE was between 1 December 1998 and

30 November 1999. An SAE is defined as ‘an adverse

experience occurring at any dose that results in any of the

following outcomes: death, life-threatening adverse drug

experience, hospitalization or prolongation of existing

hospitalization, persistent or significant disability/incapa-

city, congenital anomaly/birth defect, cancer, or overdose

(accidental or intentional). Important medical events that

may not result in death, be life-threatening, or require

hospitalization may be considered a serious adverse drug

experience when, based upon appropriate medical judg-

ment, they may jeopardize the patient, and may require

medical or surgical intervention to prevent one of the

outcomes listed in the definition above: such events should

also be reported’ (Merck & Co., Inc.).

The diagnostic categorization applied to all reported

SAE cases has been previously described (Twum-Danso

2003a, b). In this study, both ‘probable’ and ‘possible’

cases of L. loa encephalopathy temporally related to

ivermectin treatment were termed as PLERM. A ‘probable’

case was defined as follows:

• Encephalopathy (without seizures, usually with fever) in

a person previously healthy and without another

underlying cause for encephalopathy.

• Onset of progressive CNS symptoms and signs within

7 days of treatment with ivermectin illness progressing

to coma without remission.

• Peripheral blood L. loa > 10 000 mf/ml pre-treatment

or >1000 mf/ml within 1-month post-treatment or

>2700 mf/ml within 6 months of treatment; and/or

L. loa microfilariae in the CSF.

A ‘possible’ case was defined in the following manner:

• Encephalopathy (without seizures, usually with fever) in

a person previously healthy and without any other

underlying cause for encephalopathy.

• Onset of progressive CNS symptoms and signs within

7 days of treatment with ivermectin; illness progressing

to coma without remission.

• Semi-quantitative or non-quantitative positive (i.e. +, ++,

+++) L. loa microfilariae in peripheral blood within

1-month post-treatment.

Data sources

Data were obtained from: (1) retrospective chart review of

SAE reporting forms, medical records, and NGDO records

for all SAE cases that occurred in Central, Littoral and

West Province of Cameroon during the study period;

(2) review of aggregated NGDO treatment records for each

district receiving ivermectin for mass treatment of oncho-

cerciasis; and (3) structured interviews of patient and

family members from the most severely affected district in

the country (District of Okola in Central Province) about

18 months after the occurrence of the SAEs in that district.

Chart review

The following data were abstracted: demographic infor-

mation, dose of ivermectin administered, nature of symp-

toms and signs, time to onset of symptoms, time to seeking

medical help after onset of symptoms, time to transfer to a

higher acuity facility where applicable, inpatient treatment,

laboratory data including L. loa tests, hospital course




including development of any nosocomial infections,

duration of hospitalization and clinical outcome at the time

of discharge and/or at a subsequent follow-up visit.

Structured interviews

Interview questions were assessed for cultural and linguistic

appropriateness by the provincial onchocerciasis coordina-

tor from the MOPH, the chief medical doctor for the District

of Okola, and the programme coordinator of the NGDO

partner for Central Province. Because of the politico-legal

climate surrounding ivermectin treatment in Okola, the

authors were advised by several members of the NOTF to

only interview families of those who survived the adverse

event. The interviewing team consisted of the provincial

onchocerciasis coordinator, a member of the NGDO partner

for Central Province, a village guide and the first author.

On arrival in the village of residence, the patient’s home

was located by asking passers-by or the chief. If there was

no immediate recognition of the name, the fact that the

person had a serious reaction to ivermectin the previous

year was provided. If the patient could not be found they

were recorded as ‘unknown in the village’.

At the patient’s home introductions were made. The

purpose of the interview was explained to the patient and

family. Verbal informed consent was obtained for the first

author to conduct the interview and to perform a brief

neurologic exam. Permission was requested to record the

remainder of the discussion on audiotape, take written notes,

and to review the patient’s medical record if it was available

in the home. Interviews were conducted in a combination of

English, French and Eton. The patient’s name, age and

village of residence were confirmed. Past medical history and

concurrent medications prior to the onset of the SAE were

obtained. The symptoms experienced after being treated

with ivermectin, time to onset of first symptoms, and time to

seeking medical help were also elicited.

At the end of the interview, a brief neurologic exam-

ination was performed focusing on a gross assessment of

mental status, motor, sensory, and cerebellar function.

Findings from this examination provided clinical outcome

data for patients for whom no outcome data were available

in the chart review. Each patient encounter lasted for about

1 h. Because of the distances between the villages and

the time spent locating individual patients, one or two

interviews were conducted per day.

Data analysis

Data were analysed with a standard statistical software

package (The SAS System for Windows Version 8.2,

SAS Institute, Cary, NC, USA). The Wilcoxon Rank Sum

test was used to analyse continuous variables as the data

were non-parametric. Categorical data were analysed using

the v2 test or the Fisher Exact test as appropriate for sample

size. All tests were two-tailed and P was set at 0.05.

Results

Incidence of SAEs

As shown in Table 1, a total of 784 653 people were

administered ivermectin in onchocerciasis mass treatment

programmes in Central, Littoral and West Provinces of

Cameroon from 1 December 1998 to 30 November 1999.

The overall incidence of SAEs in the three provinces

studied was approximately six per 100 000 people (47 SAE

cases of a total of 784 653 people reported to have been

treated). Central Province reported the highest number

of SAE cases and had the highest incidence of SAE cases

(2.7 per 10 000; see Table 1 and Figure 1). When PLERM

cases were considered separately, again Central Province

had the highest number of cases and the highest incidence

(Table 1 and Figure 1). The most severely affected

district in Central Province was Okola with 10.5 SAEs

per 10 000 and 9.2 PLERM cases per 10 000 (Figure 2).

Demographic and clinical profile of all cases

The SAE reports and/or medical records were available for

all 47 cases. For patient interviews, 10 of the potential

20 SAE survivors from the District of Okola, Central

Province, were ultimately located. The median age of cases

was 35 (range: 6–72 years). Males represented 75% of the

caseload and 87% of cases were being treated with

ivermectin for the first time. About two-thirds of the cases

had no documented prior illness before treatment. The

temporal history from the time of administration of

ivermectin to the time of discharge from the health facility

is provided in Table 2. All 47 cases were treated as

Table 1 Number and incidence of serious adverse event (SAE)

and Probable Loa loa Encephalopathy temporally Related to

Mectizan� treatment (PLERM) cases in the study population in

Central, Littoral and West Provinces in Cameroon from1 December 1998 to 30 November 1999

Province

No. of peopletreated with

Mectizan�

No. of SAEcases (incidence

per 10 000)

No. of PLERMcases (incidence

per 10 000)

Central 132 432 36 (2.7) 25 (1.9)

Littoral 48 345 7 (1.4) 3 (0.6)

West 603 876 4 (0.07) 1 (0.02)

Total 784 653 47 29




inpatients in a clinic or hospital. The duration of hospi-

talization was not documented in eight of 47 cases. For the

remaining 39 cases, this varied from 1 day to 8 months as

shown in Table 2. The five most frequent initial symptoms

and signs experienced by patients in descending order were

as follows; the frequency of reporting is in parentheses:

1. fatigue and/or asthenia and/or difficulty or inability to

stand (43%);

2. confusion, obtundation, stupor, or unconsciousness

(26%);

3. nausea and/or vomiting and/or diarrhea and/or

dehydration (17%);

4. fever and/or chills (17%); and

5. dysarthria and/or aphasia (15%).

Table 3 illustrates the presumptive diagnostic categories

assigned to all the cases. Thirty-five of 47 cases (75%) were

given a presumptive neurologic diagnosis. Inpatient treat-

ment for all SAE cases was primarily supportive. The five

most common treatments in descending order were

LegendPLERM Non-PLERM

ProvincesCentral

1 case2 cases3 cases

1 case2 cases3 cases

LittoralWest

Figure 1 Geographical distribution of reported serious adverse

event cases temporally associated with ivermectin treatmentoccurring in Cameroon from 1 December 1998 to 30 November

1999.

0

2

4

6

8

10

12

Inci

denc

e (p

er 1

000

0)

District

0

2

4

6

8

10

HauteSanaga

NgogMapubi

Obala Okola Sa'a

Inci

denc

e (p

er 1

000

0)

(a)

(b)12

Figure 2 Reported serious adverse events from Central Province,Cameroon from 1 December 1998 to 30 November 1999.

(a) Incidence of reported SAE cases in general. (b) Incidence of

reported probable Loa loa Encephalopathy temporally Related to

Mectizan� treatment cases.

Table 2 Temporal history of serious

adverse event cases reported from

Cameroon, 1 December 1998 to

30 November 1999

Characteristics Mean (median) Range 95% CI

Time to onset of signs & symptoms (days) 1.3 (1.0) 0–4 (1.0, 1.6)

Time to seek medical help (days) 2.7 (2.5) 0–8 (1.9, 3.4)

Time to transfer to higher acuity facility,n ¼ 14 (days)

4.2 (3.5) 1–10 (2.4, 5.9)

Duration of hospitalization (days) 26.1 (14.0) 1–241 (12.8, 39.4)

Duration of hospitalization without three

most extreme outliers of >50 days (days)

16.6 (13.5) 1–50 (12.0, 21.2)




(frequency of reporting in parentheses) oral and/or intra-

venous hydration (96%); corticosteroids (intravenous or

intramuscular) (89%); multivitamins and/or vitamin B

complex and/or iron and folate supplements (65%);

analgesics and/or antipyretics and/or anti-inflammatory

agents (58%); and empirical antimalarial therapy (47%).

Antimalarial treatment was associated with worse out-

come. In the 16 cases where antimalarials were adminis-

tered, 62.5% either died or had residual neurologic deficit

while 37.5% recovered fully; P ¼ 0.006. Corticosteroid

use was associated with longer hospital stay: 27.8 days for

those who did receive steroids (n ¼ 34) vs. 3.7 days for

those who did not (n ¼ 3); P < 0.05. Insufficient data were

available to determine a differential effect of intravenous

vs. intramuscular administration of corticosteroids.

Decubitus ulcers developed in six patients during their

hospital stay, two of whom had had urinary catheters

placed, but the medical record did not indicate how early in

the hospital stay the catheters were placed and how long

they were indwelling. All six patients had been treated with

steroids.

Six of the 47 reported SAE cases died, five of whom fit

the diagnosis of PLERM. The sixth case was a mild

Mazzotti reaction in an elderly male with a history of

congestive heart failure who lived alone; his deteriorating

clinical condition was discovered and treated late. The

immediate antecedent to death in two of the cases was

septicemia from infected decubitus ulcers complicated by

hypoglycaemia in one case, and acute renal failure in the

other. The final cause of death in the other four cases

remains unclear. Neither symptoms and signs nor L. loa

microfilaremia status (qualitative and quantitative) were

predictive of clinical outcome. Data were inadequate to

analyse any association between CSF microfilarial status

(qualitative or quantitative) and clinical outcome.

Comparing cases by MSE on admission

to the health facility

Table 4 provides the demographic and clinical profiles of

patients grouped by their mental status examination on

Table 3 Presumptive diagnoses of reported serious adverse

event cases reported from Cameroon, 1 December 1998 to

30 November 1999

Presumptive diagnosis

No. of

cases (%)

Anaphylactic reaction 1 (2)

Mild Mazzotti reaction 9 (19)Neurologic 35 (75)

Probable loa encephalopathy (n ¼ 13)

Possible loa encephalopathy (n ¼ 16)Encephalopathy of other known aetiology* (n ¼ 1)

Encephalopathy of unknown aetiology (n ¼ 4)

Meningitis (n ¼ 1)

Other� 2 (4)

Total 47 (100)

* This patient had encephalopathy presumed to be due to

cerebral malaria.

� Neither patient had sufficient clinical informationdocumented to allow the assignment of presumptive diagnoses.

Table 4 Demographic and clinical profile

of serious adverse event cases reported

from Cameroon, 1 December 1998 to

30 November 1999, grouped by mentalstatus on admission to a health facility

Characteristics

Altered mental

status onadmission (n ¼ 34)

Normal mental

status onadmission (n ¼ 13)

Mean (median) age (years) 39 (35) 41 (43.5)Proportion of males (%) 79 62

First exposure to ivermectin* (%) 100 75

Mean (median) time to onset of signs &

symptoms (days)

1.2 (1.0) 1.7 (1.5)

Mean (median) time to seek

medical help (days)

2.6 (2.0) 2.9 (3.0)

Mean (median) duration of

hospitalization* (days)

30.8 (19.0) 10.7 (5.0)

Type of health facility initially sought

Clinic (%) 12 38

District (%) 76 46Central (%) 0 8

Other (%) 12 8

Proportion requiring transfer to

higher acuity facility (%)

35 15

* The value for the group with altered mental status differs from that for the groupwith normal mental status with a statistical significance of P < 0.05.




admission (MSE) to the health facility. All the patients with

altered MSE had been treated with ivermectin for the first

time, compared with 75% of patients with normal MSE.

This difference was statistically significant (P < 0.05).

Non-neurologic symptoms and signs on presentation at a

health facility for the two groups did not differ signifi-

cantly. Cases with altered MSE had a median of 2950

L. loa mf/ml of peripheral blood within 12 days post-

ivermectin administration. No pre-treatment microfilarial

counts were available for comparison. Only one case

with normal MSE on admission had quantitative L. loa

studies performed; this was 4560 mf/ml. The presumed

diagnosis in this case was mild Mazzotti reaction.

No association was found between MSE and treatment

with any single class of drugs. None of the patients

presenting with normal MSE at the health facility subse-

quently underwent a decline in mental status during

hospitalization. Consequently, none of them were assigned

a presumptive diagnosis of encephalopathy. Eighty-five

percent (29 of 34) of those with altered MSE on presen-

tation at the health facility had PLERM.

Outcome data for patients with altered MSE on

presentation at a health facility are also shown in Table 5.

Forty-five per cent of those with PLERM recovered full

neurologic function, 17% had some type of residual

neurologic deficit, 14% died, and the outcome is

unknown for the remaining 24%. Clinical outcome data

were known for eight of the 13 patients with normal

MSE: seven of these had a full recovery and one person

died. MSE was not predictive of clinical outcome.

However, it was predictive of duration of hospitalization:

patients with altered MSE stayed in the hospital

approximately three times as long as patients with normal

MSE (altered MSE: 30.8 days vs. normal MSE: 10.7 days;

P < 0.05).

Discussion

This retrospective study confirms findings from previous

studies that SAEs after administration of ivermectin in

mass treatment programmes are rare events in oncho-

cerciasis endemic areas (De Sole et al. 1989) and also in

areas co-endemic for onchocerciasis and loiasis (Gardon

et al. 1997). This is a true statement for Cameroon when

the data are viewed in aggregate. However, when the data

are further analysed, striking geographical differences

emerge. There were 47 SAE cases reported from three

L. loa endemic provinces in the central-southern region of

Cameroon during a 12-month period (Central, Littoral and

West). This represented an overall incidence of six SAEs

per 100 000 people treated for the three provinces.

However, when Central Province is considered separately

the incidence of all types of SAEs was 2.7 per 10 000, while

the incidence of PLERM was 1.9 per 10 000. The majority

of the SAEs in Central Province occurred in the District

of Okola, where the rate of all types of SAEs was

10.5 per 10 000 people treated, and that for PLERM was

9.2 per 10 000 people treated.

A prospective study conducted in Central Province found

an incidence of 12.3 per 10 000 of all types of SAEs and

1.1 per 10 000 of neurologic SAEs (Gardon et al. 1997).

The rate of all types of SAEs occurring in this study of the

District of Okola is of the same order of magnitude as that

reported in the above-referenced study in Central Province;

10.5 per 10 000 and 12.3 per 10 000 respectively. How-

ever the difference between the incidence of neurologic

SAEs is substantial (9.2 per 10 000 in this study vs. 1.1 per

10 000 in the study by Gardon et al.). This may be due to a

broader case definition: Gardon et al. considered only

‘probable’ cases with quantitative L. loa laboratory data

whereas in this retrospective study the category of

Table 5 Presumptive diagnosis and

clinical outcome of reported serious adverse

event cases with altered mental statuson admission, from Cameroon,

1 December 1998 to 30 November 1999,

n ¼ 34

Presumptive diagnosis

Clinical outcome

No. of cases (% within each diagnostic category)

Fullrecovery

Residual

neurologicdeficit Death Unknown Total

Probable Loa loa encephalopathy 7 (54) 2 (15) 3 (23) 1 (8) 13Possible Loa loa encephalopathy* 6 (38) 3 (19) 1 (6) 6 (38) 16�Encephalopathy of other

known aetiology�0 (0) 0 (0) 1 (100) 0 (0) 1

Encephalopathy of unknown aetiology 2 (50) 0 (0) 0 (0) 2 (50) 4

Total 15 5 5 9 34

* Because of rounding error, individual percentages total 101.

� This patient had encephalopathy presumed to be due to cerebral malaria.




‘possible’ cases were included so as to better capture the

reality of the standard of care in peripheral health centers

where equipment to perform quantitative laboratory

studies is often unavailable.

The fact that the rate of PLERM cases detected with an

active surveillance system in place during the incidence

study (Gardon et al. 1997) is more than eight times lower

than that found with a passive reporting system such as

that used by the MDP is compelling evidence of an

unusual epidemiologic phenomenon in Okola. It is likely

that this high rate of PLERM correlates with a high

prevalence of individuals with high L. loa microfilarial

loads (>10 000 mf/ml pre-treatment) in this population,

however the current study was unable to show this

relationship because of its retrospective design. Quanti-

tative laboratory data were not available for patients

presenting at health facilities with intact mentation, or for

the general population treated in the mass treatment

programme but not suffering an adverse event. Previously

published data support this inference, however, as the

prevalence of L. loa microfilaremia in certain parts of

Central Province is estimated to be as high as 38%

(Boussinesq & Gardon 1997) and recent studies con-

ducted in Cameroon report a high correlation between

prevalence and intensity of infection (Boussinesq et al.

2001).

These issues need to be viewed in light of several

important limitations of the study. Its retrospective design

in a clinical setting where there is incomplete and incon-

sistent documentation in the medical record imposed

significant constraints on which variables could be ana-

lysed as many data were missing. Also, most of the

hospitals do not keep medical records on site – they

accompany the patient upon discharge and patients do not

necessarily keep them in a safe place. Furthermore, as the

post-treatment surveillance system in place was passive,

the true numerator of SAE cases remains unknown. But the

denominator of the number of people treated with

ivermectin is relatively reliable.

There are also several potential biases in this study.

A selection bias could have been introduced because only

half of the target number of 20 patients was ultimately

located for interviews. Additionally, the potential for recall

bias on the part of the patient and family members is

important to note because the SAEs occurred 18 months

prior to the interview. Furthermore it is likely that SAEs

may have been under-reported because of the following

reasons: (1) surveillance for SAEs during the study period

was passive, (2) given the long distances from some villages

to the nearest health facility, many patients may not have

come to medical attention, and (3) even when the case was

treated at a health facility, reporting of the case and

submission of forms to the MOPH and the MDP was

sometimes poor and inconsistent.

These limitations notwithstanding, some important

results of this study are worth highlighting. First, consistent

with previously published literature on this topic, males

were more likely than females to develop a CNS distur-

bance following ivermectin treatment in this study (Duong

et al. 1997; Boussinesq et al. 1998) assuming a 1:1 ratio of

males to females treated in the community (data were not

available to assess the actual ratio because the treatment

data were not reported by gender groupings). Although this

difference was not found to be statistically significant in

this study, this may be due to the small sample size.

Secondly, individuals being treated with ivermectin for

the first time were statistically more likely to develop

PLERM. This is consistent with the observation that

PLERM occurs in individuals with high levels of L. loa

microfilaremia (Gardon et al. 1997). Ivermectin is known

to be effective against the microfilariae of L. loa, causing a

decline in the microfilarial load (Martin-Prevel et al. 1993),

the rapidity of which has been temporally related to the

development of neurologic sequelae (Boussinesq et al.

1998). After repeated rounds of ivermectin treatment

intensity of infection has been shown to decrease (Kombila

et al. 1998), thus presumably reducing the risk of PLERM.

One putative mechanism proposed for the pathogenesis of

PLERM is the development of microinfarcts because of

dying microfilariae themselves or their degradation prod-

ucts as ivermectin treatment has been associated with the

passage of L. loa microfilariae into the CSF (Ducorps et al.

1995) and with sub-conjunctival and retinal haemorrhages

in people with high L. loa microfilarial loads (Fobi et al.

2000).

Thirdly, symptoms and signs of the SAE, including

encephalopathy, were likely to occur within the first 48 h

after treatment. However, it took about 2–3 days for the

patient to come to medical attention. This study was not

designed to address the reasons for this delay. Possible

explanations may be that family members may have had a

‘wait and see’ approach as symptoms tended to be

progressive in severity. Alternatively, distance from health

care facilities, costs associated with transportation, tem-

porary relocation away from the village and leaving the

farm unattended, and non-reimbursable costs associated

with hospitalization may have played a deterrent role.

This has several important implications for programme

operations: (i) surveillance for SAEs needs to be intensi-

fied in the first 48 h after treatment while maintaining the

same recommended duration of 7 days particularly in

ivermectin-naıve populations; (ii) the surveillance and

referral system of SAEs in the community needs to

formally include family members, and not just the




community drug distributors and health personnel who

may not always be available; (iii) barriers to seeking

medical help when an SAE occurs need to be investigated

and removed where possible.

Fourthly, the observation that treatment with anti-

malarial drugs was associated with poor clinical outcome is

surprising and somewhat difficult to explain. Confounding

factors not addressed in this retrospective study would

need to be considered in future studies to determine the

significance of this.

Lastly, and probably most importantly, is the finding of

increased risk of PLERM in the District of Okola

compared with other ivermectin-naıve populations treated

in other L. loa endemic areas of Cameroon or other L. loa

endemic countries of Central and West Africa (MDP

unpublished data). It is possible that this epidemiologic

pattern could be explained by factors other than the

intensity of infection with L. loa. Differences in the strain

of the L. loa parasite or its vector, Chrysops spp., may alter

the pathogenesis of the disease, particularly with respect to

the CNS. The influence of dietary or environmental factors

unique to Okola may also be a possible explanation but

this is perhaps less likely as the inhabitants of neighboring

districts have similar cultural and dietary practices and live

in ecologically similar environments. Other potential

candidates include the active ingredients of the locally

brewed alcohol, which anecdotally have been associated

with an increased risk of encephalopathy following

ivermectin treatment.

An alternative hypothesis is that this clinical phenom-

enon may be a manifestation of increased susceptibility

to ivermectin because of deficiency or alteration in

P-glycoprotein (PGP) or other membrane proteins in the

blood–brain barrier (BBB) that function as drug efflux

transporters. PGP, which is encoded by the mdr gene, has

been shown to be a multi-drug efflux transporter in normal

brain capillary endothelial cells (Tatsuta et al. 1992;

Tsuji et al. 1992) whose substrates include lipophilic

substances such as ivermectin (Tamai & Tsuji 2000),

consistent with the observation that ivermectin does not

normally cross the BBB at therapeutic doses. Thus, if PGP

was found to be absent or deficient in certain individuals

within a population group, it is likely that they would be

susceptible to the neurotoxic effects of ivermectin as has

been demonstrated in mdr1a knockout mice (Schinkel

et al. 1994) and mdr1 knockout Collie dogs (Mealey et al.

2001). As ivermectin is believed to potentiate gamma

aminobutyric acid, a suppressive neurotransmitter (Lankas

& Gordon 1989), it would presumably have a diffuse

suppressive effect on neurones if it were to achieve high

concentrations in the brain, consistent with the encephalo-

pathic nature of most of the reported neurologic SAEs.

However, this explanation for the focality of disease in

Okola would only be plausible if the people of Okola had a

mutation in the gene that encodes PGP in humans (MDR1)

or other gene(s) that encode(s) other drug efflux transpor-

ter(s) of the BBB. As yet, there is no evidence to support

this theory in humans.

Reporting bias may also play a role; for example over-

reporting from Okola or conversely, under-reporting from

other districts may explain some of the observed variation.

As part of the policy for mass treatment with ivermectin,

communities are informed of possible side effects and are

told that any post-treatment effects of ivermectin would be

treated free of charge. This policy, although ethical,

introduces an element of complexity into the situation for

three reasons: (1) some district medical officers and NGDO

staff reported that the population is not used to being

warned about side effects to any drug, thus any symptoms

following treatment are likely to be attributed to ivermec-

tin treatment, (2) pre-existing conditions such as ‘signifi-

cant fatigue’ may be considered an SAE without any

diagnostic work-up, and (3) SAEs were treated free of

charge whereas patients had to pay for the treatment of

minor adverse events; so it was beneficial to the patient and

the treating physician to label the illness as an SAE rather

than as a minor adverse event, an understandable beha-

viour in a setting where the population is materially poor

and health care is often unaffordable.

This apparent increased risk of encephalopathic SAEs in

Okola has had far-reaching implications on the success of

onchocerciasis control strategies in Okola itself, neigh-

bouring districts, and perhaps neighbouring provinces. The

affected communities’ perception of the risks and benefits

associated with ivermectin treatment has been negatively

altered (Ndonko 1999). Since 1999 the acceptance of the

mass treatment programme in Central Province has

declined even in areas with high prevalence of oncho-

cerciasis (Haselow et al. 2003). If this trend continues, it is

likely to seriously jeopardize the overall success of the OCP

in Cameroon and the international effort to eliminate

onchocerciasis as a public health problem in Africa.

A related concern may be a secondary impact on other

public health programmes. As the same health staff and

community health workers are typically involved in other

public health programmes in the community, it is possible

that those too, might be negatively affected by association.

Additionally, the costs associated with SAE identifica-

tion, referral, and inpatient hospitalization are not trivial.

The MOPH of Cameroon, the NGDOs, the patients and

family members all bear the financial burden of SAEs in one

way or the other, be it direct medical costs or indirect costs

such as lost income, time lost from work, residual neuro-

logic deficit or death (Twum-Danso, unpublished data).




In the absence of a screening tool for detecting individ-

uals with high L. loa microfilaremia, mass treatment of

onchocerciasis with ivermectin continues to be based on a

risk-benefit assessment at the community level. In order to

address the increased reporting of PLERM cases from

Cameroon, the Mectizan� Expert Committee, in colla-

boration with the Technical Consultative Committee of

APOC, changed its recommendations for mass treatment

of onchocerciasis with ivermectin in L. loa endemic areas

(Mectizan� Expert Committee 2000). Namely, in areas

with a prevalence of onchocerciasis of 40% or more (thus

eligible for mass treatment), if the majority of the popu-

lation is expected to be naıve to ivermectin, the following

measures must be implemented in all communities before

mass treatment begins: determination of the prevalence of

onchocerciasis on a village-by-village level rather than on a

sample of villages in an area, enhanced health education,

surveillance, referral and evacuation of SAE cases to health

facilities, and also training of health staff at peripheral and

central levels on the appropriate clinical management of

SAE cases. The rationale behind these recommendations is

early detection and treatment of any SAE that may occur

(albeit a rare event), while ensuring that communities with

high prevalence of onchocerciasis receive their needed

annual dose of ivermectin to prevent progression of

onchorcecal blindness and skin disease.

Reducing the risk of PLERM is obviously the most

appropriate solution to this problem. Practically, this may

be achieved by excluding communities which have a

L. loa prevalence higher than a given threshold, as

community prevalence is correlated with the prevalence of

individuals with high intensity infection (Boussinesq et al.

2001). This strategy would potentially reduce the chances

of treating individuals at increased risk of PLERM because

of high intensity L. loa microfilaremia. However, a

substantial proportion of the population with severe

onchocerciasis or at high risk of onchocerciasis may be

excluded regardless of whether they were co-infected with

L. loa or not. If it were possible to perform mass screening

of individuals, rather than communities, with high inten-

sity L. loa microfilaremia, significant progress could be

made in reducing the risk of PLERM without limiting the

benefits of ivermectin to those with, or at risk of,

onchocerciasis. Performing blood smears on all eligible

members of the communities in conjunction with mass

treatment is programmatically difficult and perhaps

impossible in some settings. The need for a laboratory

technician, microscope, lancets with their attendant risks

of transmission of human immunodeficiency virus and

hepatitis B virus, makes this option somewhat impractical.

The new rapid assessment tool of identifying L. loa

endemic communities by history of passage of an

eye-worm, which is currently being field-tested, promises

to be an effective tool for screening communities at risk

for development of PLERM (Takougang et al. 2002).

However, further studies are needed to refine these rapid

screening tools such that they can be used at the level of

the individual so that people who would otherwise benefit

from ivermectin treatment for onchocerciasis control are

not excluded when their community is found to have high

prevalence of loiasis.

Acknowledgements

We are very grateful to the National Onchocerciasis Task

Force and the NGDO Coalition for Onchocerciasis

Control of Cameroon without whom this study could

never have been conducted. In particular, we would like to

thank Drs Michel Boussinesq, Agnes Esiene, and Domi-

nique Noah for making their medical records available for

review. We would also like to thank Helen Keller Inter-

national/Cameroon for providing us with office space

during the part of the study performed in Cameroon. In

addition, we would like to thank Mrs Julie Akame,

Mr Cyrille Evini and Mr Lambert Mentong a Dang for

all their assistance with field activities. Finally, we are

grateful to Drs Philip Coyne, Marc Karam and Erica Frank

for their editorial input and to Mr Flavien Ake for mapping

the SAE cases with Geographical Information System

software.

Funding for this work was provided by the Rollins

School of Public Health, Emory University, Atlanta, GA,

USA in the form of the William H. & Anne E. Foege

Global Health Scholarship, and by the Mectizan�

Donation Program, Atlanta, GA, USA.

Conflict of interest

The fieldwork was partially funded by the Mectizan�

Donation Program (MDP) and SEOM worked for the

MDP at the time of the study; NAYTD is now employed by

the MDP.

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Authors

Dr Nana A. Y. Twum-Danso, Mectizan� Donation Program, 750 Commerce Drive, Suite 400, Decatur, GA 30030, USA.

Tel.: +1 404 371 1460; Fax: +1 404 371 1138; E-mail: [email protected] (corresponding author).

Dr Stefanie E. O. Meredith, Mectizan� Donation Program, 750 Commerce Drive, Suite 400, Decatur, GA 30030, USA.

Tel.: +1 404 371 1460; Fax: +1 404 371 1138; E-mail: [email protected]




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Variation in incidence of serious adverse events after onchocerciasis treatment with ivermectin in areas of Cameroon co-endemic for loiasis