Background This study was designed to examine the knowledge, attitude and beliefs about causes, manifestations and treatment of mental illness among adults in a rural community in northern Nigeria.
Background
This study was designed to examine the knowledge, attitude and beliefs about causes, manifestations and treatment of mental illness among adults in a rural community in northern Nigeria.Methods A cross sectional study design was used. A pre-tested, semi-structured questionnaire was administered to 250 adults residing in Karfi village, northern Nigeria.
Methods
A cross sectional study design was used. A pre-tested, semi-structured questionnaire was administered to 250 adults residing in Karfi village, northern Nigeria.Results The most common symptoms proffered by respondents as manifestations of mental illness included aggression/destructiveness (22.0%), loquaciousness (21.2%), eccentric behavior (16.1%) and wandering (13.3%). Drug misuse including alcohol, cannabis, and other street drugs was identified in 34.3% of the responses as a major cause of mental illness, followed by divine wrath/ God's will (19%), and magic/spirit possession (18.0%). About 46% of respondents preferred orthodox medical care for the mentally sick while 34% were more inclined to spiritual healing. Almost half of the respondents harbored negative feelings towards the mentally ill. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects (OR = 7.6, 95% confidence interval = 3.8–15.1).
Results
The most common symptoms proffered by respondents as manifestations of mental illness included aggression/destructiveness (22.0%), loquaciousness (21.2%), eccentric behavior (16.1%) and wandering (13.3%). Drug misuse including alcohol, cannabis, and other street drugs was identified in 34.3% of the responses as a major cause of mental illness, followed by divine wrath/ God's will (19%), and magic/spirit possession (18.0%). About 46% of respondents preferred orthodox medical care for the mentally sick while 34% were more inclined to spiritual healing. Almost half of the respondents harbored negative feelings towards the mentally ill. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects (OR = 7.6, 95% confidence interval = 3.8–15.1).Conclusions Our study demonstrates the need for community educational programs in Nigeria aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons.
Conclusions
Our study demonstrates the need for community educational programs in Nigeria aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons.

Background Throughout the world, there is an increasing awareness of mental illness as a significant cause of morbidity [ 1 ]. This awareness has increased with the steady decline of morbidity due to nutritional disorders, communicable diseases and other forms of physical illness, especially in countries undergoing epidemiological transition [ 2 ]. Mental and behavioral disorders are common, affecting more than 25% of all people at some time during their lives [ 3 ]. They are also universal, affecting people of all countries and societies, regardless of age, gender and income. The point prevalence of mental illness in the adult population at any given time is about 10% [ 3 ]. Similarly, around 20% of all patients seen by primary health care providers have one or more mental health disorders [ 3 ]. The role of the community in the prevention and care of the mentally handicapped has now been widely acknowledged and is regarded as the most appropriate basis for the development of mental health programs. Several studies have shown that knowledge of public attitude to mental illness and its treatment is a vitally important prerequisite to the realization of successful community-based programs [ 4 - 6 ]. The recognition of mental disorder also depends on a careful evaluation of the norms, beliefs and customs within the individual's cultural environment. Furthermore, community attitude and beliefs play a role in determining help-seeking behavior and successful treatment of the mentally ill. Unarguably, ignorance and stigma prevent the mentally ill from seeking appropriate help. People tend to have strong beliefs about the mentally ill, and many of these concepts are based on prevailing local systems of belief [ 7 ]. In developing any mental health education program, the basis of such beliefs must be taken into consideration. People's beliefs regarding mental illness should not only be known, but the purpose of their beliefs should be understood. Such attitudes and beliefs about mental illness can only be studied within a cultural context. Although the knowledge and perception of mentally ill patients and their relatives regarding mental illness has been reported from southwest Nigeria [ 8 ], to date there is little research on public attitudes towards mental illness from northern Nigeria, a culturally distinct part of the country. This paper is therefore one of the first to report findings related to attitudinal research on mental illness from northern Nigeria. The 1995 Nigeria National Mental Health Policy advocates the integration of mental health promotion, treatment and rehabilitation into primary health care services (PHC). However, this goal cannot be successfully achieved without an understanding of community attitudes towards mental illness. We therefore set out to ascertain the perceptions, attitudes and beliefs of adults regarding the causes, manifestations and treatment options of mental illness in a traditional Hausa community near Kano, Nigeria.
Background
Throughout the world, there is an increasing awareness of mental illness as a significant cause of morbidity [ 1 ]. This awareness has increased with the steady decline of morbidity due to nutritional disorders, communicable diseases and other forms of physical illness, especially in countries undergoing epidemiological transition [ 2 ].Mental and behavioral disorders are common, affecting more than 25% of all people at some time during their lives [ 3 ]. They are also universal, affecting people of all countries and societies, regardless of age, gender and income. The point prevalence of mental illness in the adult population at any given time is about 10% [ 3 ]. Similarly, around 20% of all patients seen by primary health care providers have one or more mental health disorders [ 3 ].The role of the community in the prevention and care of the mentally handicapped has now been widely acknowledged and is regarded as the most appropriate basis for the development of mental health programs. Several studies have shown that knowledge of public attitude to mental illness and its treatment is a vitally important prerequisite to the realization of successful community-based programs [ 4 - 6 ]. The recognition of mental disorder also depends on a careful evaluation of the norms, beliefs and customs within the individual's cultural environment. Furthermore, community attitude and beliefs play a role in determining help-seeking behavior and successful treatment of the mentally ill. Unarguably, ignorance and stigma prevent the mentally ill from seeking appropriate help.People tend to have strong beliefs about the mentally ill, and many of these concepts are based on prevailing local systems of belief [ 7 ]. In developing any mental health education program, the basis of such beliefs must be taken into consideration. People's beliefs regarding mental illness should not only be known, but the purpose of their beliefs should be understood. Such attitudes and beliefs about mental illness can only be studied within a cultural context. Although the knowledge and perception of mentally ill patients and their relatives regarding mental illness has been reported from southwest Nigeria [ 8 ], to date there is little research on public attitudes towards mental illness from northern Nigeria, a culturally distinct part of the country. This paper is therefore one of the first to report findings related to attitudinal research on mental illness from northern Nigeria.The 1995 Nigeria National Mental Health Policy advocates the integration of mental health promotion, treatment and rehabilitation into primary health care services (PHC). However, this goal cannot be successfully achieved without an understanding of community attitudes towards mental illness. We therefore set out to ascertain the perceptions, attitudes and beliefs of adults regarding the causes, manifestations and treatment options of mental illness in a traditional Hausa community near Kano, Nigeria.Methods Study area The study population included 250 adults residing at Karfi village, about 15 kilometers from Kano city. This typical Hausa community has 11,314 inhabitants [ 9 ]. Majority are Muslims preoccupied with farming and petty trading. About 32.0% of the populace are literate. The village has one primary health centre and several traditional healers. Referrals from the health centers are sent to Kura General Hospital and occasionally to Aminu Kano Teaching Hospital. Informed consent was obtained from respondents prior to commencement of the interviews. Study design A cross sectional descriptive study Sample size and sampling technique A multistage sampling technique was adopted. In the first stage, four wards out of the seven in the village were randomly selected. After house numbering, 250 houses were selected from the four wards using a table of random numbers. Where more than one household was found in a house, one household was selected by balloting. Finally, one adult was selected at random from each household for the interview. A final sample size of 250 adults was therefore obtained. Instrument description/ Data collection We adopted and modified a pre-existing semi-structured questionnaire [ 7 ] to evaluate the perceptions and beliefs of adults in Karfi village. The questionnaire was in three parts; the first section inquired about personal data including age, sex, ethnicity, religion, marital status, educational level and occupation; the second part elicited awareness of existence of mental illness in the community, knowledge of causal factors, manifestation of the disorder and awareness and preference of treatment options, while the third part explored the attitudes, beliefs and perception of the respondent towards the mentally ill. Attitudes such as fear, avoidance, anger, suspicion, mistrust, hostility were considered negative, whereas sympathetic attitude, willingness to care for a mentally ill relative or friend and tolerance were considered positive attitudes. The study instrument was validated using a pilot study of 10 randomly selected households in a nearby village with similar demographic characteristics (Kumbotso). Results of the pilot study were used to modify content and wording of the questionnaire. Previously trained medical undergraduates fluent in Hausa language administered the questionnaires to the sample population. Data analysis The data was analyzed using the Epi-Info ®  6.0 statistical software package (CDC Atlanta, Georgia, USA). Descriptive statistics were depicted using absolute numbers, simple percentages, range, and measures of central tendency (mean, median) as appropriate. The Chi-square test was used to test the significance of associations between categorical groups. All tests of hypothesis were two-tailed with a type 1 error rate fixed at 5%.
Methods
Study area The study population included 250 adults residing at Karfi village, about 15 kilometers from Kano city. This typical Hausa community has 11,314 inhabitants [ 9 ]. Majority are Muslims preoccupied with farming and petty trading. About 32.0% of the populace are literate. The village has one primary health centre and several traditional healers. Referrals from the health centers are sent to Kura General Hospital and occasionally to Aminu Kano Teaching Hospital. Informed consent was obtained from respondents prior to commencement of the interviews.
Study area
The study population included 250 adults residing at Karfi village, about 15 kilometers from Kano city. This typical Hausa community has 11,314 inhabitants [ 9 ]. Majority are Muslims preoccupied with farming and petty trading. About 32.0% of the populace are literate. The village has one primary health centre and several traditional healers. Referrals from the health centers are sent to Kura General Hospital and occasionally to Aminu Kano Teaching Hospital. Informed consent was obtained from respondents prior to commencement of the interviews.Study design A cross sectional descriptive study
Study design
A cross sectional descriptive studySample size and sampling technique A multistage sampling technique was adopted. In the first stage, four wards out of the seven in the village were randomly selected. After house numbering, 250 houses were selected from the four wards using a table of random numbers. Where more than one household was found in a house, one household was selected by balloting. Finally, one adult was selected at random from each household for the interview. A final sample size of 250 adults was therefore obtained.
Sample size and sampling technique
A multistage sampling technique was adopted. In the first stage, four wards out of the seven in the village were randomly selected. After house numbering, 250 houses were selected from the four wards using a table of random numbers. Where more than one household was found in a house, one household was selected by balloting. Finally, one adult was selected at random from each household for the interview. A final sample size of 250 adults was therefore obtained.Instrument description/ Data collection We adopted and modified a pre-existing semi-structured questionnaire [ 7 ] to evaluate the perceptions and beliefs of adults in Karfi village. The questionnaire was in three parts; the first section inquired about personal data including age, sex, ethnicity, religion, marital status, educational level and occupation; the second part elicited awareness of existence of mental illness in the community, knowledge of causal factors, manifestation of the disorder and awareness and preference of treatment options, while the third part explored the attitudes, beliefs and perception of the respondent towards the mentally ill. Attitudes such as fear, avoidance, anger, suspicion, mistrust, hostility were considered negative, whereas sympathetic attitude, willingness to care for a mentally ill relative or friend and tolerance were considered positive attitudes. The study instrument was validated using a pilot study of 10 randomly selected households in a nearby village with similar demographic characteristics (Kumbotso). Results of the pilot study were used to modify content and wording of the questionnaire. Previously trained medical undergraduates fluent in Hausa language administered the questionnaires to the sample population.
Instrument description/ Data collection
We adopted and modified a pre-existing semi-structured questionnaire [ 7 ] to evaluate the perceptions and beliefs of adults in Karfi village. The questionnaire was in three parts; the first section inquired about personal data including age, sex, ethnicity, religion, marital status, educational level and occupation; the second part elicited awareness of existence of mental illness in the community, knowledge of causal factors, manifestation of the disorder and awareness and preference of treatment options, while the third part explored the attitudes, beliefs and perception of the respondent towards the mentally ill. Attitudes such as fear, avoidance, anger, suspicion, mistrust, hostility were considered negative, whereas sympathetic attitude, willingness to care for a mentally ill relative or friend and tolerance were considered positive attitudes.The study instrument was validated using a pilot study of 10 randomly selected households in a nearby village with similar demographic characteristics (Kumbotso). Results of the pilot study were used to modify content and wording of the questionnaire. Previously trained medical undergraduates fluent in Hausa language administered the questionnaires to the sample population.Data analysis The data was analyzed using the Epi-Info ®  6.0 statistical software package (CDC Atlanta, Georgia, USA). Descriptive statistics were depicted using absolute numbers, simple percentages, range, and measures of central tendency (mean, median) as appropriate. The Chi-square test was used to test the significance of associations between categorical groups. All tests of hypothesis were two-tailed with a type 1 error rate fixed at 5%.
Data analysis
The data was analyzed using the Epi-Info ®  6.0 statistical software package (CDC Atlanta, Georgia, USA). Descriptive statistics were depicted using absolute numbers, simple percentages, range, and measures of central tendency (mean, median) as appropriate. The Chi-square test was used to test the significance of associations between categorical groups. All tests of hypothesis were two-tailed with a type 1 error rate fixed at 5%.Results In all, 250 respondents were interviewed with 167 males and 83 females giving a sex ratio of 2:1 in favor of males. Their ages ranged from 18 to 74 years. Majority (78.0%) of the respondents were aged between 25 and 60 years. The median age (± SD) for the respondents was 34.5 ± 4.6 years; 36.0 ± 2.3 years for males and 28.5 ± 1.6 years for females. The Hausa-Fulani ethnic group constituted 89% of respondents, and the rest were Yoruba 2.0%, Igbo 5.0% and other minority Nigerian tribes 4.0%. About 16.0% of respondents had primary education, 12.0% had secondary education, and 4.0% had tertiary (post-secondary school) education. Approximately 27.0% of the population sampled had no formal education. Nevertheless, 41.0% of all respondents had Quranic education. The majority of respondents (90.0%) were Muslims and the remaining 10.0% were Christians. About 10.0% were single, 80.0% were married, 6.0% were divorced and the remaining 4.0% were widowed. Forty eight per cent of the respondents were engaged in farming, 25.0% were full-time housewives, 20.0% were engaged in petty trading, 7.0% were students and the remaining 4.0% were civil servants. About 13 persons interviewed (5.2%) had a relative with mental illness, but because of the small sample size we did not separately analyze findings from this group of participants. The most common symptoms proffered by respondents as manifestations of mental illness (Table  1 ) included aggression/destructiveness (22.0%), talkativeness (21.2%), eccentric behaviour (16.1%), and wandering (13.3%). Drug misuse in form of alcohol ingestion, cannabis and other psychoactive street drugs were identified as major causes of mental illness (34.3%), followed by effect of divine wrath or God's will (18.8%), magic or spirit possession (18.0%), and accidents/trauma (11.7%) (Table  2 ). Heredity, family conflicts and financial distress/poverty were uncommon responses. Table 1 Respondents' perceived manifestations of mental disorder Manifestation No.* (%) Rank order Aggression/destructiveness 173 (22.0) 1 Talkativeness 167 (21.2) 2 Eccentric behavior 127 (16.1) 3 Wandering 105 (13.3) 4 Self-neglect 86 (10.9) 5 Nudity 56 (7.1) 6 Restlessness/anxiety 50 (6.4) 7 Insomnia 15 (1.9) 8 Loss of consciousness 8 (1.0) 9 * Multiple responses recorded. Percentages represent proportions of responses obtained. Table 2 Perceived causes of mental illness Perceived cause No.* (%) Rank Misuse of drugs † 88 (34.3) 1 Divine punishment, God's will 48 (18.8) 2 Magic, spirit possession 46 (18.0) 3 Accidents/trauma 30 (11.7) 4 Heredity 27 (10.5) 5 Family conflicts/marital disharmony 14 (5.5) 6 Financial distress/poverty 3 (1.2) 7 *Multiple responses recorded.  †  Include street drugs and alcohol. The majority of respondents (46.0%) opted for orthodox medical care when asked about preferred source of treatment for the mentally ill. This was followed by spiritual healing (exorcism) (34.0%) and the use of traditional herbal medicines (18.0%) (Table  3 ). Table 3 Respondents' preferred treatment for mental illness Response No. (%) Orthodox Medicine 116 (46.0) Traditional Medicine 46 (18.0) Spiritual Healing 85 (34.0) Others 3 (2.0) Total 250 (100.0) Table  4  shows that majority of the respondents harbored negative feelings towards the mentally ill, mainly in the form of fear (n = 113) and avoidance (n = 81). A total of 117 respondents (46.8%) were sympathetic towards the plight of the mentally sick with female respondents showing more inclination for sympathy compared to their male counterparts. The female respondents, however, tend to be fearful and avoid the mentally sick more than their male counterparts. Table 4 Distribution of attitude towards the mentally ill by gender Attitude Male Female Total No. (%) No. (%) Fear 24 (20.8) 89 (79.2) 113 Avoidance 12 (14.4) 69 (85.6) 81 Anger 48 (96.8) 2 (3.2) 50 Suspicion 36 (90.4) 4 (9.6) 40 Hostility 32 (93.6) 3 (6.4) 35 Mistrust 28 (89.6) 4 (10.4) 32 Indifference 16 (96.0) 1 (4.0) 17 Sympathy 39 (33.6) 78 (66.4) 117 Kindness 17 (20.8) 62 (79.2) 79 Literacy status was significantly associated with the type of feeling exhibited by the participants. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects (OR = 7.6, 95% confidence interval = 3.8–15.1) (Table  5 ). Table 5 Influence of literacy level of respondents on attitude towards the mentally ill Positive attitude Negative attitude Total Odds ratio (95%CI)* Literate 92 15 107 7.6 (3.8–15.1) Not literate 64 79 143 Total 156 94 250 *CI = confidence interval, p < 0.0001
Results
In all, 250 respondents were interviewed with 167 males and 83 females giving a sex ratio of 2:1 in favor of males. Their ages ranged from 18 to 74 years. Majority (78.0%) of the respondents were aged between 25 and 60 years. The median age (± SD) for the respondents was 34.5 ± 4.6 years; 36.0 ± 2.3 years for males and 28.5 ± 1.6 years for females. The Hausa-Fulani ethnic group constituted 89% of respondents, and the rest were Yoruba 2.0%, Igbo 5.0% and other minority Nigerian tribes 4.0%. About 16.0% of respondents had primary education, 12.0% had secondary education, and 4.0% had tertiary (post-secondary school) education. Approximately 27.0% of the population sampled had no formal education. Nevertheless, 41.0% of all respondents had Quranic education. The majority of respondents (90.0%) were Muslims and the remaining 10.0% were Christians. About 10.0% were single, 80.0% were married, 6.0% were divorced and the remaining 4.0% were widowed. Forty eight per cent of the respondents were engaged in farming, 25.0% were full-time housewives, 20.0% were engaged in petty trading, 7.0% were students and the remaining 4.0% were civil servants. About 13 persons interviewed (5.2%) had a relative with mental illness, but because of the small sample size we did not separately analyze findings from this group of participants.The most common symptoms proffered by respondents as manifestations of mental illness (Table  1 ) included aggression/destructiveness (22.0%), talkativeness (21.2%), eccentric behaviour (16.1%), and wandering (13.3%). Drug misuse in form of alcohol ingestion, cannabis and other psychoactive street drugs were identified as major causes of mental illness (34.3%), followed by effect of divine wrath or God's will (18.8%), magic or spirit possession (18.0%), and accidents/trauma (11.7%) (Table  2 ). Heredity, family conflicts and financial distress/poverty were uncommon responses.Respondents' perceived manifestations of mental disorderManifestationNo.* (%)Rank order* Multiple responses recorded. Percentages represent proportions of responses obtained.Perceived causes of mental illnessPerceived causeNo.* (%)Rank*Multiple responses recorded.  †  Include street drugs and alcohol.The majority of respondents (46.0%) opted for orthodox medical care when asked about preferred source of treatment for the mentally ill. This was followed by spiritual healing (exorcism) (34.0%) and the use of traditional herbal medicines (18.0%) (Table  3 ).Respondents' preferred treatment for mental illnessResponseNo. (%)Table  4  shows that majority of the respondents harbored negative feelings towards the mentally ill, mainly in the form of fear (n = 113) and avoidance (n = 81). A total of 117 respondents (46.8%) were sympathetic towards the plight of the mentally sick with female respondents showing more inclination for sympathy compared to their male counterparts. The female respondents, however, tend to be fearful and avoid the mentally sick more than their male counterparts.Distribution of attitude towards the mentally ill by genderAttitudeMaleFemaleTotalLiteracy status was significantly associated with the type of feeling exhibited by the participants. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects (OR = 7.6, 95% confidence interval = 3.8–15.1) (Table  5 ).Influence of literacy level of respondents on attitude towards the mentally illPositive attitudeNegative attitudeTotalOdds ratio (95%CI)**CI = confidence interval, p < 0.0001Discussion Aggression/destructiveness, talkativeness, and eccentric behaviors were the most frequently mentioned perceived symptoms of mental illness by respondents. This finding suggests that one has to display behaviour that attracts public attention and is therefore socially disruptive, to be recognized as having a mental disorder. This finding is similar to that documented by White in Tanzania [ 10 ] and Asuni  et al . [ 7 ] among Yoruba patients in Western Nigeria. It is notable that hallucinations and delusions that are frequently mentioned in the literature as prototypes of gross psychotic states were not mentioned by the respondents as features of mental illness, probably because such features are not as tangible as aggressive attitudes. Misuse of drugs ranked highest among the respondents as a perceived cause of mental disorders than most of the other traditional etiologies. This finding may not be unconnected with increasing use of illicit drugs among the youth in developing countries. Although drug abuse was acknowledged by Iliyasu and Last [ 11 ] in their work on mental illness in Kano, northern Nigeria as a leading cause of drug dependent psychosis, Holzinger and colleagues [ 12 ] reported that drugs and alcohol was not considered by schizophrenia patients or their relatives to be a common cause of mental illness. Divine punishment ranked second as a perceived causative factor. This response may not be unconnected with the leading response (drug misuse), as many individuals are of the belief that one evokes supernatural wrath by taking intoxicants thus leading to the development of mental illness [ 3 ]. Belief in demons as the cause of mental health problems is a well-known phenomenon in many cultures of the world [ 13 ] but in our study this factor was ranked 3 rd  place by respondents (18% of the responses). Our finding is also in contrast to Adebowale and Ogunlesi [ 8 ] who found that "supernatural causes" were the most acceptable etiological factor among both mentally ill patients and their relatives in southwest Nigeria. Only 1.0% of respondents admitted that financial distress or poverty was a possible cause of mental disorder. Such a low score in the face of the present adverse socio-economic conditions prevailing in Nigeria may be explained by the Hausa cultural cum religious belief in providence and patience in the face of adversity. Other factors have also been reported by investigators as being associated with perceived causes of mental illness among patients and their relatives. Srinivasan and Thara [ 14 ] found that patient gender and education, duration of illness, the key relative's education, and the nature of relationship were associated with family beliefs about the cause of mental illness. There was a higher score on the preference for modern medical care in treating psychiatric illness. Similar changes in attitude towards the modern scientific approach regarding mental disorders was documented by Alem et al [ 15 ] in their work on mental illness in Ethiopia and by Iliyasu and Last [ 11 ]. Fear and avoidance of the mentally sick was frequent among female respondents. Traditionally, men are expected to be outwardly brave and less submissive towards aggression. The high frequency of negative attitudes among our respondents may be due to the fact that the concept of the mentally sick has an unfavourable public image. It has been shown that people may evaluate mental illness negatively, reject and discriminate against mental patients, and base their views on traditional stereotypes [ 4 , 10 , 16 ]. Literacy was found to be significantly associated with positive attitude towards the mentally sick. Similar findings were reported by Madianos  et al . [ 17 ] in Greece, and by Alem  et al . [ 15 ] in Ethiopia. A study on community attitudes towards the mentally ill in New Zealand also reported that those who had previous contact with the mentally ill held informed and enlightened views [ 18 ]. Interestingly, a recent Hong Kong study reported a generally negative attitude towards the mentally ill despite a fairly good knowledge of mental illness among the respondents [ 19 ]. Our results support the hypothesis by Wolff  et al . [ 19 ] that negative attitudes towards the mentally ill are fuelled by a lack of knowledge.
Discussion
Aggression/destructiveness, talkativeness, and eccentric behaviors were the most frequently mentioned perceived symptoms of mental illness by respondents. This finding suggests that one has to display behaviour that attracts public attention and is therefore socially disruptive, to be recognized as having a mental disorder. This finding is similar to that documented by White in Tanzania [ 10 ] and Asuni  et al . [ 7 ] among Yoruba patients in Western Nigeria. It is notable that hallucinations and delusions that are frequently mentioned in the literature as prototypes of gross psychotic states were not mentioned by the respondents as features of mental illness, probably because such features are not as tangible as aggressive attitudes.et alMisuse of drugs ranked highest among the respondents as a perceived cause of mental disorders than most of the other traditional etiologies. This finding may not be unconnected with increasing use of illicit drugs among the youth in developing countries. Although drug abuse was acknowledged by Iliyasu and Last [ 11 ] in their work on mental illness in Kano, northern Nigeria as a leading cause of drug dependent psychosis, Holzinger and colleagues [ 12 ] reported that drugs and alcohol was not considered by schizophrenia patients or their relatives to be a common cause of mental illness. Divine punishment ranked second as a perceived causative factor. This response may not be unconnected with the leading response (drug misuse), as many individuals are of the belief that one evokes supernatural wrath by taking intoxicants thus leading to the development of mental illness [ 3 ].Belief in demons as the cause of mental health problems is a well-known phenomenon in many cultures of the world [ 13 ] but in our study this factor was ranked 3 rd  place by respondents (18% of the responses). Our finding is also in contrast to Adebowale and Ogunlesi [ 8 ] who found that "supernatural causes" were the most acceptable etiological factor among both mentally ill patients and their relatives in southwest Nigeria.Only 1.0% of respondents admitted that financial distress or poverty was a possible cause of mental disorder. Such a low score in the face of the present adverse socio-economic conditions prevailing in Nigeria may be explained by the Hausa cultural cum religious belief in providence and patience in the face of adversity. Other factors have also been reported by investigators as being associated with perceived causes of mental illness among patients and their relatives. Srinivasan and Thara [ 14 ] found that patient gender and education, duration of illness, the key relative's education, and the nature of relationship were associated with family beliefs about the cause of mental illness.There was a higher score on the preference for modern medical care in treating psychiatric illness. Similar changes in attitude towards the modern scientific approach regarding mental disorders was documented by Alem et al [ 15 ] in their work on mental illness in Ethiopia and by Iliyasu and Last [ 11 ].Fear and avoidance of the mentally sick was frequent among female respondents. Traditionally, men are expected to be outwardly brave and less submissive towards aggression. The high frequency of negative attitudes among our respondents may be due to the fact that the concept of the mentally sick has an unfavourable public image. It has been shown that people may evaluate mental illness negatively, reject and discriminate against mental patients, and base their views on traditional stereotypes [ 4 , 10 , 16 ].Literacy was found to be significantly associated with positive attitude towards the mentally sick. Similar findings were reported by Madianos  et al . [ 17 ] in Greece, and by Alem  et al . [ 15 ] in Ethiopia. A study on community attitudes towards the mentally ill in New Zealand also reported that those who had previous contact with the mentally ill held informed and enlightened views [ 18 ]. Interestingly, a recent Hong Kong study reported a generally negative attitude towards the mentally ill despite a fairly good knowledge of mental illness among the respondents [ 19 ]. Our results support the hypothesis by Wolff  et al . [ 19 ] that negative attitudes towards the mentally ill are fuelled by a lack of knowledge.et alet alet alConclusions This study demonstrates the need for educational programs aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Our findings may be of utility to health policy makers in the design of community mental health education programs and community mental health services in existing primary health centers in Nigeria.
Conclusions
This study demonstrates the need for educational programs aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Our findings may be of utility to health policy makers in the design of community mental health education programs and community mental health services in existing primary health centers in Nigeria.Competing interests None declared.
Competing interests
None declared.Authors' Contributions KM and IZ initiated the study, and participated in the field work. IZ and AIS did the preliminary analysis and wrote the draft manuscript. KM, AIS and IZ participated in the design of the study and performed the statistical analysis. KM, IZ, and AIS participated in its design and coordination. AMH, KM and IZ wrote the final version of the draft manuscript. All authors read and approved the final manuscript.
Authors' Contributions
KM and IZ initiated the study, and participated in the field work. IZ and AIS did the preliminary analysis and wrote the draft manuscript. KM, AIS and IZ participated in the design of the study and performed the statistical analysis. KM, IZ, and AIS participated in its design and coordination. AMH, KM and IZ wrote the final version of the draft manuscript. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Background Pneumocystis pneumonia (PCP) is an increasing problem amongst patients on immunosuppression with autoimmune inflammatory disorders (AID). The disease presents acutely and its diagnosis requires bronchoalveolar lavage in most cases. Despite treatment with intravenous antibiotics, PCP carries a worse prognosis in AID patients than HIV positive patients. The overall incidence of PCP in patients with AID remains low, although patients with Wegener's granulomatosis are at particular risk.
Background
Pneumocystis pneumonia (PCP) is an increasing problem amongst patients on immunosuppression with autoimmune inflammatory disorders (AID). The disease presents acutely and its diagnosis requires bronchoalveolar lavage in most cases. Despite treatment with intravenous antibiotics, PCP carries a worse prognosis in AID patients than HIV positive patients. The overall incidence of PCP in patients with AID remains low, although patients with Wegener's granulomatosis are at particular risk.Discussion In adults with AID, the risk of PCP is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis.
Discussion
In adults with AID, the risk of PCP is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis.Summary Corticosteroids, lymphopenia and a low CD4+ count in particular, have been identified as risk factors for the development of PCP in adults with AID. Trimethoprim-sulfamethoxazole (co-trimoxazole) is an effective prophylactic agent, but indications for its use remain ill-defined. Further prospective trials are required to validate our proposed prevention strategy.
Summary
Corticosteroids, lymphopenia and a low CD4+ count in particular, have been identified as risk factors for the development of PCP in adults with AID. Trimethoprim-sulfamethoxazole (co-trimoxazole) is an effective prophylactic agent, but indications for its use remain ill-defined. Further prospective trials are required to validate our proposed prevention strategy.

Background Pneumocystis carinii was identified a hundred years ago by Chagas [ 1 ] and recognised as a pathogen in marasmic children at the end of World War II [ 2 ]. The organism came to the fore again in the early 1980s when apparently healthy homosexual men developed PCP and heralded the acquired immunodeficiency syndrome (AIDS) epidemic [ 3 ]. With highly active antiretroviral therapy (HAART) and prophylactic antibiotics, attention has turned to PCP in human immunodeficiency virus (HIV) negative individuals. We recently treated a young woman with steroid-based immunosuppression for dermatomyositis. Four months after diagnosis, she was admitted acutely breathless to the intensive care unit with a presumptive diagnosis of PCP. Although the final diagnosis was rapidly progressive alveolitis related to dematomyositis, it prompted us to consider whether we should use PCP prophylaxis for selected patients receiving systemic steroids for AID. In this article we explore the background of PCP in HIV negative patients, consider the incidence of PCP in AID, discuss predisposing factors and propose a strategy for prevention. Epidemiology Pneumocystis pneumonia is caused in humans by the recently renamed Pneumocystis jiroveci (Frenkel 1999), previously known as Pneumocystis carinii and now thought to be related to fungi on the basis of DNA analysis, despite morphological similarities to protozoa [ 4 ]. The organism shows significant genetic divergence and is host specific with no cross-species infectivity. There has been considerable debate about the nature of the relationship between humans and P. jiroveci. At one time it was hypothesised that infection occurred through reactivation of colonisation acquired in childhood, as specific antibody was found in seven out of eight normal adults [ 5 ]. This suggestion has been refuted by the absence of detectable P. jiroveci in bronchoalveolar lavage specimens from healthy volunteers, despite amplification by the polymerase chain reaction [ 6 ]. In addition, genotypic analysis of P. jiroveci from infected adults identified strains found in patients' place of residence, rather than their place of birth [ 7 ]. Investigation of apparent clusters has shown different genetic strains affecting most cases, indicating that transmission from affected cases to susceptible persons does not account for the majority of infections [ 8 , 9 ], despite the recognised transmission of Pneumocystis DNA from affected patients to their immunocompetent contact health care workers to produce colonisation [ 10 ]. As P. jiroveci has been isolated in samples of air [ 11 ] and pond water [ 12 ], it is likely that the environment represents the main source of infection for most patients. Nevertheless, isolation of known cases of PCP is advisable. Pneumocystis pneumonia is almost always exclusive to immunocompromised hosts. Two thirds of cases occur in HIV positive patients and constitutes the initial manifestation of AIDS in 46% of these patients [ 13 ]. A third of cases arise in HIV negative patients [ 14 ], a group consisting of organ transplant recipients (0–75%), haematological malignancies (9–58%), solid organ tumours (4–17.5%) and AID, usually on immunosuppressive treatment. The latter group accounts for 13–36% of cases in HIV negative patients [ 15 - 19 ]. It is this group we wish to consider in more detail. Pathogenesis P. jiroveci trophozoites proliferate and attach to type I alveolar pneumocytes causing desquamation, leading to a foamy eosinophilic exudate visible on hematoxylin-eosin staining and a "honey comb" appearance of lung tissue. Both antibody and cell mediated immunity have been postulated as being involved in host protection [ 20 ]. Clinical presentation HIV-negative patients with PCP are older (48–61 years) than HIV positive patients. Males are affected more often than females (male to female ratio 1:1.4). The clinical course is typically more acute, with an average duration of 6–13 days. The most frequent clinical symptoms are dyspnoea (63–100%), cough (55–74%), weakness (47%), loss of appetite (38%) expectoration (22–25%), sweating (19%), weight loss (13%), haemoptysis (9%) and thoracic pain (9%). Physical findings include fever >38°C (63–85%), râles (55–66%), tachycardia (25%) and tachypnoea (22%). Chest radiography may show bilateral abnormalities (68–88%), interstitial opacities (64–80%) and alveolar opacities (31–47%), but may be normal (5–7%) [ 14 - 16 , 18 , 21 ]. The clinical picture can be altered by the use of aerosolised pentamidine prophylaxis, resulting in extra-pulmonary disease [ 20 ]. P. jiroveci in HIV negative patients is associated with concurrent pulmonary infections in over 50% of cases. The implicated pathogens include Cytomegalovirus (35%), Candida (18%) and Mycobacterium tuberculosis, which contribute significantly to the mortality of PCP [ 17 , 18 , 22 ]. Diagnosis P. jiroveci infection is diagnosed in most cases by bronchoalveolar lavage, which, depending on the staining method used, has been reported to have a sensitivity of 81 to 90% and a specificity of 90 to 100% [ 23 ]. Other methods used include hypertonic saline induced sputum production, which is less sensitive, and definitive open lung biopsy. Cysts or trophozoites are morphologically identified by methenamine-silver nitrate or giemsa stains respectively. Immunospecific stains are now available and have increased the sensitivity of detection in sputum and bronchoalveolar lavage fluid [ 24 ]. The number of organisms in diagnostic specimens is high in HIV positive patients, but often low in HIV negative cases. An induced sputum sample may therefore be insufficient in the latter situation and bronchoalveolar lavage and/or transbronchial biopsy is the preferred method of investigation [ 20 ]. In patients who are at risk of PCP it is essential to have a high index of suspicion and low threshold for investigation, to allow early diagnosis and treatment. This is particularly important in those with AID, as PCP may mimic pulmonary involvement by the underlying condition, such as dermatomyositis, as exemplified by our patient who prompted this review. In SLE, 33% of patients die from infections, with 62.5% of all fatal infections being opportunistic, but only 10% of opportunistic pathogens are detected ante-mortem [ 25 ]. Management Two antibiotic regimes have been shown to work, co-trimoxazole and parenteral pentamidine isethionate. Efficacies are comparable, although side-effects are particularly common with co-trimoxazole in HIV associated PCP and affect up to 60% of such patients [ 26 ]. These include rash, neutropenia, gastrointestinal upset and liver enzyme disturbance. Although side-effects are less common with parenteral pentamidine, toxicity tends to be more severe and includes pancreatitis, hypoglycaemia, neutropenia, thrombocytopenia and orthostatic hypotension. Treatment with co-trimoxazole is usually given for 21 days in HIV cases and 14 days in HIV negative PCP. Co-trimoxazole is used in 90% of cases of PCP [ 15 ] and is associated with fewer reactions (15%) in HIV negative patients [ 22 ]. Prognosis The prognosis of HIV negative PCP is worse than for those HIV positive, with intensive care admission in 31–60%; mechanical ventilation in 14–64%; overall mortality 19–47%, rising to 50–71% on intensive care, although some series suggest an improved mortality in recent years [ 14 - 18 , 27 ]. Poor prognosis has been associated with tachypnoea, tachycardia, elevated C-reactive protein, raised lactate dehydrogenase, mechanical ventilation, and some studies suggest a correlation with previous mean steroid dose and treatment with cyclophosphamide [ 17 , 18 ]. The mortality rate of patients with underlying AID appears to be worse than for other HIV negative patients [ 15 ] and varies according to underlying pathology: 63% in Wegener's granulomatosis; 58% in inflammatory myopathy; 48% in polyarteritis nodosa; 31% in rheumatoid arthritis and 17% in systemic sclerosis [ 27 ]. Several case reports suggest that PCP in inflammatory myopathy may follow a fulminant course [ 28 ]. While PCP in HIV positive patients has been associated with a high incidence of relapse after successful therapy, this has not been seen in patients with AID, even without secondary prophylaxis and despite ongoing immunosuppressive treatment. This is thought to be related to better clearance of organism, confirmed by repeat bronchoalveolar lavage [ 22 ]. Incidence There is no specific surveillance system in the United Kingdom (UK) for PCP, other than in HIV infection. Although laboratories are invited to report isolates of P. jiroveci to the Communicable Disease Surveillance Centre, it is estimated that only a fifth of clinically diagnosed cases of PCP are reported [ 29 ]. As the laboratory-reported number of cases was 0.36 per million in 1999, we would estimate the true incidence of PCP to be approximately 1.8 per million in that year. While Pneumocystis is the second commonest reported invasive mycosis, this estimate suggests that PCP is still a rare pathogen in the UK. The overall incidence of PCP from 1990 to 1999 has declined in the UK [ 29 ], as a result of the advent of HAART for AIDS. However, probably as a result of the use of ever more immunosuppressive therapy, the number of cases of PCP diagnosed in HIV negative patients increased throughout the 1980s and 1990s [ 14 - 16 , 18 , 27 ]. These two opposing trends have resulted in HIV negative patients constituting an ever increasing proportion of the total number of cases of PCP. Attempts have been made to characterise the incidence of PCP amongst patients with AID, usually by retrospective analysis of case records. Ward & Donald's review of 223 cases of PCP in AID is the largest series and covered 2.6 million hospitalisations over the period 1983 to 1994 [ 27 ]. They found the underlying AID in this group to be SLE (42%), rheumatoid arthritis (18%), Wegener's granulomatosis (14%), inflammatory myopathy (12%), polyarteritis nodosa (9%) and systemic sclerosis (5%). An estimate of the incidence of PCP in a particular AID was derived by determining the number of cases of PCP in a particular AID per 1,000 hospitalisations with the said AID per year. The results were: 8.9/1,000 hospitalisations /year for Wegener's granulomatosis; 6.5 for polyarteritis nodosa; 2.7 for inflammatory myopathy; 1.2 for SLE; 0.8 for systemic sclerosis and 0.2 for rheumatoid arthritis. Clearly the denominator in these frequencies reflects hospital admissions per year with a particular AID. For an AID where the average annual rate of admission is less than once per year, the true incidence for that condition will be less than the rate quoted and vice versa. These frequencies, with the exception of polyarteritis nodosa, are broadly comparable with findings in other studies which report a long-term risk of PCP of 6–12% for Wegener's granulomatosis and less than 2% for other AID [ 14 , 22 , 30 ]. There are only a few isolated reports of PCP in dermatoses treated with medium-term systemic steroids such as pemphigus, pemphigoid, cutaneous necrotizing vasculitis and Behçet's syndrome [ 22 , 31 ].
Background
Pneumocystis carinii was identified a hundred years ago by Chagas [ 1 ] and recognised as a pathogen in marasmic children at the end of World War II [ 2 ]. The organism came to the fore again in the early 1980s when apparently healthy homosexual men developed PCP and heralded the acquired immunodeficiency syndrome (AIDS) epidemic [ 3 ]. With highly active antiretroviral therapy (HAART) and prophylactic antibiotics, attention has turned to PCP in human immunodeficiency virus (HIV) negative individuals. We recently treated a young woman with steroid-based immunosuppression for dermatomyositis. Four months after diagnosis, she was admitted acutely breathless to the intensive care unit with a presumptive diagnosis of PCP. Although the final diagnosis was rapidly progressive alveolitis related to dematomyositis, it prompted us to consider whether we should use PCP prophylaxis for selected patients receiving systemic steroids for AID. In this article we explore the background of PCP in HIV negative patients, consider the incidence of PCP in AID, discuss predisposing factors and propose a strategy for prevention.Epidemiology Pneumocystis pneumonia is caused in humans by the recently renamed Pneumocystis jiroveci (Frenkel 1999), previously known as Pneumocystis carinii and now thought to be related to fungi on the basis of DNA analysis, despite morphological similarities to protozoa [ 4 ]. The organism shows significant genetic divergence and is host specific with no cross-species infectivity. There has been considerable debate about the nature of the relationship between humans and P. jiroveci. At one time it was hypothesised that infection occurred through reactivation of colonisation acquired in childhood, as specific antibody was found in seven out of eight normal adults [ 5 ]. This suggestion has been refuted by the absence of detectable P. jiroveci in bronchoalveolar lavage specimens from healthy volunteers, despite amplification by the polymerase chain reaction [ 6 ]. In addition, genotypic analysis of P. jiroveci from infected adults identified strains found in patients' place of residence, rather than their place of birth [ 7 ]. Investigation of apparent clusters has shown different genetic strains affecting most cases, indicating that transmission from affected cases to susceptible persons does not account for the majority of infections [ 8 , 9 ], despite the recognised transmission of Pneumocystis DNA from affected patients to their immunocompetent contact health care workers to produce colonisation [ 10 ]. As P. jiroveci has been isolated in samples of air [ 11 ] and pond water [ 12 ], it is likely that the environment represents the main source of infection for most patients. Nevertheless, isolation of known cases of PCP is advisable. Pneumocystis pneumonia is almost always exclusive to immunocompromised hosts. Two thirds of cases occur in HIV positive patients and constitutes the initial manifestation of AIDS in 46% of these patients [ 13 ]. A third of cases arise in HIV negative patients [ 14 ], a group consisting of organ transplant recipients (0–75%), haematological malignancies (9–58%), solid organ tumours (4–17.5%) and AID, usually on immunosuppressive treatment. The latter group accounts for 13–36% of cases in HIV negative patients [ 15 - 19 ]. It is this group we wish to consider in more detail.
Epidemiology
Pneumocystis pneumonia is caused in humans by the recently renamed Pneumocystis jiroveci (Frenkel 1999), previously known as Pneumocystis carinii and now thought to be related to fungi on the basis of DNA analysis, despite morphological similarities to protozoa [ 4 ]. The organism shows significant genetic divergence and is host specific with no cross-species infectivity. There has been considerable debate about the nature of the relationship between humans and P. jiroveci. At one time it was hypothesised that infection occurred through reactivation of colonisation acquired in childhood, as specific antibody was found in seven out of eight normal adults [ 5 ]. This suggestion has been refuted by the absence of detectable P. jiroveci in bronchoalveolar lavage specimens from healthy volunteers, despite amplification by the polymerase chain reaction [ 6 ]. In addition, genotypic analysis of P. jiroveci from infected adults identified strains found in patients' place of residence, rather than their place of birth [ 7 ]. Investigation of apparent clusters has shown different genetic strains affecting most cases, indicating that transmission from affected cases to susceptible persons does not account for the majority of infections [ 8 , 9 ], despite the recognised transmission of Pneumocystis DNA from affected patients to their immunocompetent contact health care workers to produce colonisation [ 10 ]. As P. jiroveci has been isolated in samples of air [ 11 ] and pond water [ 12 ], it is likely that the environment represents the main source of infection for most patients. Nevertheless, isolation of known cases of PCP is advisable.Pneumocystis pneumonia is almost always exclusive to immunocompromised hosts. Two thirds of cases occur in HIV positive patients and constitutes the initial manifestation of AIDS in 46% of these patients [ 13 ]. A third of cases arise in HIV negative patients [ 14 ], a group consisting of organ transplant recipients (0–75%), haematological malignancies (9–58%), solid organ tumours (4–17.5%) and AID, usually on immunosuppressive treatment. The latter group accounts for 13–36% of cases in HIV negative patients [ 15 - 19 ]. It is this group we wish to consider in more detail.Pathogenesis P. jiroveci trophozoites proliferate and attach to type I alveolar pneumocytes causing desquamation, leading to a foamy eosinophilic exudate visible on hematoxylin-eosin staining and a "honey comb" appearance of lung tissue. Both antibody and cell mediated immunity have been postulated as being involved in host protection [ 20 ].
Pathogenesis
P. jiroveci trophozoites proliferate and attach to type I alveolar pneumocytes causing desquamation, leading to a foamy eosinophilic exudate visible on hematoxylin-eosin staining and a "honey comb" appearance of lung tissue. Both antibody and cell mediated immunity have been postulated as being involved in host protection [ 20 ].Clinical presentation HIV-negative patients with PCP are older (48–61 years) than HIV positive patients. Males are affected more often than females (male to female ratio 1:1.4). The clinical course is typically more acute, with an average duration of 6–13 days. The most frequent clinical symptoms are dyspnoea (63–100%), cough (55–74%), weakness (47%), loss of appetite (38%) expectoration (22–25%), sweating (19%), weight loss (13%), haemoptysis (9%) and thoracic pain (9%). Physical findings include fever >38°C (63–85%), râles (55–66%), tachycardia (25%) and tachypnoea (22%). Chest radiography may show bilateral abnormalities (68–88%), interstitial opacities (64–80%) and alveolar opacities (31–47%), but may be normal (5–7%) [ 14 - 16 , 18 , 21 ]. The clinical picture can be altered by the use of aerosolised pentamidine prophylaxis, resulting in extra-pulmonary disease [ 20 ]. P. jiroveci in HIV negative patients is associated with concurrent pulmonary infections in over 50% of cases. The implicated pathogens include Cytomegalovirus (35%), Candida (18%) and Mycobacterium tuberculosis, which contribute significantly to the mortality of PCP [ 17 , 18 , 22 ].
Clinical presentation
HIV-negative patients with PCP are older (48–61 years) than HIV positive patients. Males are affected more often than females (male to female ratio 1:1.4). The clinical course is typically more acute, with an average duration of 6–13 days. The most frequent clinical symptoms are dyspnoea (63–100%), cough (55–74%), weakness (47%), loss of appetite (38%) expectoration (22–25%), sweating (19%), weight loss (13%), haemoptysis (9%) and thoracic pain (9%). Physical findings include fever >38°C (63–85%), râles (55–66%), tachycardia (25%) and tachypnoea (22%). Chest radiography may show bilateral abnormalities (68–88%), interstitial opacities (64–80%) and alveolar opacities (31–47%), but may be normal (5–7%) [ 14 - 16 , 18 , 21 ]. The clinical picture can be altered by the use of aerosolised pentamidine prophylaxis, resulting in extra-pulmonary disease [ 20 ]. P. jiroveci in HIV negative patients is associated with concurrent pulmonary infections in over 50% of cases. The implicated pathogens include Cytomegalovirus (35%), Candida (18%) and Mycobacterium tuberculosis, which contribute significantly to the mortality of PCP [ 17 , 18 , 22 ].Diagnosis P. jiroveci infection is diagnosed in most cases by bronchoalveolar lavage, which, depending on the staining method used, has been reported to have a sensitivity of 81 to 90% and a specificity of 90 to 100% [ 23 ]. Other methods used include hypertonic saline induced sputum production, which is less sensitive, and definitive open lung biopsy. Cysts or trophozoites are morphologically identified by methenamine-silver nitrate or giemsa stains respectively. Immunospecific stains are now available and have increased the sensitivity of detection in sputum and bronchoalveolar lavage fluid [ 24 ]. The number of organisms in diagnostic specimens is high in HIV positive patients, but often low in HIV negative cases. An induced sputum sample may therefore be insufficient in the latter situation and bronchoalveolar lavage and/or transbronchial biopsy is the preferred method of investigation [ 20 ]. In patients who are at risk of PCP it is essential to have a high index of suspicion and low threshold for investigation, to allow early diagnosis and treatment. This is particularly important in those with AID, as PCP may mimic pulmonary involvement by the underlying condition, such as dermatomyositis, as exemplified by our patient who prompted this review. In SLE, 33% of patients die from infections, with 62.5% of all fatal infections being opportunistic, but only 10% of opportunistic pathogens are detected ante-mortem [ 25 ].
Diagnosis
P. jiroveci infection is diagnosed in most cases by bronchoalveolar lavage, which, depending on the staining method used, has been reported to have a sensitivity of 81 to 90% and a specificity of 90 to 100% [ 23 ]. Other methods used include hypertonic saline induced sputum production, which is less sensitive, and definitive open lung biopsy. Cysts or trophozoites are morphologically identified by methenamine-silver nitrate or giemsa stains respectively. Immunospecific stains are now available and have increased the sensitivity of detection in sputum and bronchoalveolar lavage fluid [ 24 ]. The number of organisms in diagnostic specimens is high in HIV positive patients, but often low in HIV negative cases. An induced sputum sample may therefore be insufficient in the latter situation and bronchoalveolar lavage and/or transbronchial biopsy is the preferred method of investigation [ 20 ]. In patients who are at risk of PCP it is essential to have a high index of suspicion and low threshold for investigation, to allow early diagnosis and treatment. This is particularly important in those with AID, as PCP may mimic pulmonary involvement by the underlying condition, such as dermatomyositis, as exemplified by our patient who prompted this review. In SLE, 33% of patients die from infections, with 62.5% of all fatal infections being opportunistic, but only 10% of opportunistic pathogens are detected ante-mortem [ 25 ].Management Two antibiotic regimes have been shown to work, co-trimoxazole and parenteral pentamidine isethionate. Efficacies are comparable, although side-effects are particularly common with co-trimoxazole in HIV associated PCP and affect up to 60% of such patients [ 26 ]. These include rash, neutropenia, gastrointestinal upset and liver enzyme disturbance. Although side-effects are less common with parenteral pentamidine, toxicity tends to be more severe and includes pancreatitis, hypoglycaemia, neutropenia, thrombocytopenia and orthostatic hypotension. Treatment with co-trimoxazole is usually given for 21 days in HIV cases and 14 days in HIV negative PCP. Co-trimoxazole is used in 90% of cases of PCP [ 15 ] and is associated with fewer reactions (15%) in HIV negative patients [ 22 ].
Management
Two antibiotic regimes have been shown to work, co-trimoxazole and parenteral pentamidine isethionate. Efficacies are comparable, although side-effects are particularly common with co-trimoxazole in HIV associated PCP and affect up to 60% of such patients [ 26 ]. These include rash, neutropenia, gastrointestinal upset and liver enzyme disturbance. Although side-effects are less common with parenteral pentamidine, toxicity tends to be more severe and includes pancreatitis, hypoglycaemia, neutropenia, thrombocytopenia and orthostatic hypotension. Treatment with co-trimoxazole is usually given for 21 days in HIV cases and 14 days in HIV negative PCP. Co-trimoxazole is used in 90% of cases of PCP [ 15 ] and is associated with fewer reactions (15%) in HIV negative patients [ 22 ].Prognosis The prognosis of HIV negative PCP is worse than for those HIV positive, with intensive care admission in 31–60%; mechanical ventilation in 14–64%; overall mortality 19–47%, rising to 50–71% on intensive care, although some series suggest an improved mortality in recent years [ 14 - 18 , 27 ]. Poor prognosis has been associated with tachypnoea, tachycardia, elevated C-reactive protein, raised lactate dehydrogenase, mechanical ventilation, and some studies suggest a correlation with previous mean steroid dose and treatment with cyclophosphamide [ 17 , 18 ]. The mortality rate of patients with underlying AID appears to be worse than for other HIV negative patients [ 15 ] and varies according to underlying pathology: 63% in Wegener's granulomatosis; 58% in inflammatory myopathy; 48% in polyarteritis nodosa; 31% in rheumatoid arthritis and 17% in systemic sclerosis [ 27 ]. Several case reports suggest that PCP in inflammatory myopathy may follow a fulminant course [ 28 ]. While PCP in HIV positive patients has been associated with a high incidence of relapse after successful therapy, this has not been seen in patients with AID, even without secondary prophylaxis and despite ongoing immunosuppressive treatment. This is thought to be related to better clearance of organism, confirmed by repeat bronchoalveolar lavage [ 22 ].
Prognosis
The prognosis of HIV negative PCP is worse than for those HIV positive, with intensive care admission in 31–60%; mechanical ventilation in 14–64%; overall mortality 19–47%, rising to 50–71% on intensive care, although some series suggest an improved mortality in recent years [ 14 - 18 , 27 ]. Poor prognosis has been associated with tachypnoea, tachycardia, elevated C-reactive protein, raised lactate dehydrogenase, mechanical ventilation, and some studies suggest a correlation with previous mean steroid dose and treatment with cyclophosphamide [ 17 , 18 ]. The mortality rate of patients with underlying AID appears to be worse than for other HIV negative patients [ 15 ] and varies according to underlying pathology: 63% in Wegener's granulomatosis; 58% in inflammatory myopathy; 48% in polyarteritis nodosa; 31% in rheumatoid arthritis and 17% in systemic sclerosis [ 27 ]. Several case reports suggest that PCP in inflammatory myopathy may follow a fulminant course [ 28 ].While PCP in HIV positive patients has been associated with a high incidence of relapse after successful therapy, this has not been seen in patients with AID, even without secondary prophylaxis and despite ongoing immunosuppressive treatment. This is thought to be related to better clearance of organism, confirmed by repeat bronchoalveolar lavage [ 22 ].Incidence There is no specific surveillance system in the United Kingdom (UK) for PCP, other than in HIV infection. Although laboratories are invited to report isolates of P. jiroveci to the Communicable Disease Surveillance Centre, it is estimated that only a fifth of clinically diagnosed cases of PCP are reported [ 29 ]. As the laboratory-reported number of cases was 0.36 per million in 1999, we would estimate the true incidence of PCP to be approximately 1.8 per million in that year. While Pneumocystis is the second commonest reported invasive mycosis, this estimate suggests that PCP is still a rare pathogen in the UK. The overall incidence of PCP from 1990 to 1999 has declined in the UK [ 29 ], as a result of the advent of HAART for AIDS. However, probably as a result of the use of ever more immunosuppressive therapy, the number of cases of PCP diagnosed in HIV negative patients increased throughout the 1980s and 1990s [ 14 - 16 , 18 , 27 ]. These two opposing trends have resulted in HIV negative patients constituting an ever increasing proportion of the total number of cases of PCP. Attempts have been made to characterise the incidence of PCP amongst patients with AID, usually by retrospective analysis of case records. Ward & Donald's review of 223 cases of PCP in AID is the largest series and covered 2.6 million hospitalisations over the period 1983 to 1994 [ 27 ]. They found the underlying AID in this group to be SLE (42%), rheumatoid arthritis (18%), Wegener's granulomatosis (14%), inflammatory myopathy (12%), polyarteritis nodosa (9%) and systemic sclerosis (5%). An estimate of the incidence of PCP in a particular AID was derived by determining the number of cases of PCP in a particular AID per 1,000 hospitalisations with the said AID per year. The results were: 8.9/1,000 hospitalisations /year for Wegener's granulomatosis; 6.5 for polyarteritis nodosa; 2.7 for inflammatory myopathy; 1.2 for SLE; 0.8 for systemic sclerosis and 0.2 for rheumatoid arthritis. Clearly the denominator in these frequencies reflects hospital admissions per year with a particular AID. For an AID where the average annual rate of admission is less than once per year, the true incidence for that condition will be less than the rate quoted and vice versa. These frequencies, with the exception of polyarteritis nodosa, are broadly comparable with findings in other studies which report a long-term risk of PCP of 6–12% for Wegener's granulomatosis and less than 2% for other AID [ 14 , 22 , 30 ]. There are only a few isolated reports of PCP in dermatoses treated with medium-term systemic steroids such as pemphigus, pemphigoid, cutaneous necrotizing vasculitis and Behçet's syndrome [ 22 , 31 ].
Incidence
There is no specific surveillance system in the United Kingdom (UK) for PCP, other than in HIV infection. Although laboratories are invited to report isolates of P. jiroveci to the Communicable Disease Surveillance Centre, it is estimated that only a fifth of clinically diagnosed cases of PCP are reported [ 29 ]. As the laboratory-reported number of cases was 0.36 per million in 1999, we would estimate the true incidence of PCP to be approximately 1.8 per million in that year. While Pneumocystis is the second commonest reported invasive mycosis, this estimate suggests that PCP is still a rare pathogen in the UK.The overall incidence of PCP from 1990 to 1999 has declined in the UK [ 29 ], as a result of the advent of HAART for AIDS. However, probably as a result of the use of ever more immunosuppressive therapy, the number of cases of PCP diagnosed in HIV negative patients increased throughout the 1980s and 1990s [ 14 - 16 , 18 , 27 ]. These two opposing trends have resulted in HIV negative patients constituting an ever increasing proportion of the total number of cases of PCP.Attempts have been made to characterise the incidence of PCP amongst patients with AID, usually by retrospective analysis of case records. Ward & Donald's review of 223 cases of PCP in AID is the largest series and covered 2.6 million hospitalisations over the period 1983 to 1994 [ 27 ]. They found the underlying AID in this group to be SLE (42%), rheumatoid arthritis (18%), Wegener's granulomatosis (14%), inflammatory myopathy (12%), polyarteritis nodosa (9%) and systemic sclerosis (5%). An estimate of the incidence of PCP in a particular AID was derived by determining the number of cases of PCP in a particular AID per 1,000 hospitalisations with the said AID per year. The results were: 8.9/1,000 hospitalisations /year for Wegener's granulomatosis; 6.5 for polyarteritis nodosa; 2.7 for inflammatory myopathy; 1.2 for SLE; 0.8 for systemic sclerosis and 0.2 for rheumatoid arthritis. Clearly the denominator in these frequencies reflects hospital admissions per year with a particular AID. For an AID where the average annual rate of admission is less than once per year, the true incidence for that condition will be less than the rate quoted and vice versa. These frequencies, with the exception of polyarteritis nodosa, are broadly comparable with findings in other studies which report a long-term risk of PCP of 6–12% for Wegener's granulomatosis and less than 2% for other AID [ 14 , 22 , 30 ]. There are only a few isolated reports of PCP in dermatoses treated with medium-term systemic steroids such as pemphigus, pemphigoid, cutaneous necrotizing vasculitis and Behçet's syndrome [ 22 , 31 ].Discussion Pneumocystis pneumonia in AID is unusual in the absence of steroid treatment. Corticosteroids have been recently administered in over 90% of cases in most series [ 14 , 17 , 18 , 22 ] and were the sole immunosuppressant in 17–28% of AID patients [ 18 , 22 ]. The median duration of treatment prior to the diagnosis of PCP is three to four months. Occurrence within a month of starting treatment is uncommon, with the exception of inflammatory myopathies [ 28 , 32 ]. Most cases have taken prednisolone in excess of 15 mg per day, or equivalent doses of corticosteroid. Notable is the profound inter-subject variation in response to standard steroid doses as measured by in vitro inhibition of lymphocyte proliferation [ 33 ], indicating that host factors are likely to have a significant, but as yet ill-defined role. Several mechanisms have been postulated to explain the role of steroids in promoting the development of P. jiroveci including CD4+ lymphocyte depletion and immune dysfunction [ 17 , 30 ]. Porges et al. found an association between the risk of PCP and the dose of prednisone used in SLE [ 32 ]. Similarly, Hellman et al. found an association between prednisolone dosage and risk of fatal opportunistic infection in SLE, the commonest cause of which was P. jiroveci [ 26 ]. However, other studies have failed to show an association between cumulative steroid dose and risk of PCP [ 34 ]. A number of cytotoxic and other immunosuppressive agents commonly used in the treatment of AID are frequently associated with PCP, including cyclophosphamide, azathioprine, methotrexate and ciclosporin [ 14 ]. Cyclophosphamide is routinely used in the treatment of Wegener's granulomatosis and has transformed the previous one year survival figure of 20% [ 35 ] into the present eight year survival of 80% [ 36 ]. Godeau et al. [ 34 ] showed a significant association between cyclophosphamide cumulative dose and the risk of PCP. However, this was not an independent factor in multivariate analysis when lymphopenia was taken into account [ 19 ]. In one series involving 180 patients with Wegener's granulomatosis, no cases of PCP were identified amongst patients on cytotoxic therapy alone (although the authors did not specify the numbers involved), suggesting a permissive role for corticosteroids [ 30 ]. Data on PCP associated with AID indicates lymphocytopenia (<1,000 cells/mm 3 ) is almost a prerequisite, with 91% of patients exhibiting a low lymphocyte count. Fifty percent of such PCP patients have total lymphocyte counts of <400 cells/mm 3  [ 22 ]. The pre-treatment lymphocyte count and lymphocyte counts during the first three months of immunosuppressive treatment in Wegener's granulomatosis have been shown to be predictive for PCP in multivariate analysis. A total lymphocyte count <600 cells/mm 3  was recorded in ten (83%) of 12 patients with PCP, but such a low lymphocyte count was recorded in 11 (34%) of 32 with Wegener's unaffected by PCP [ 34 ]. A similar association was found in a prospective study involving patients with SLE [ 37 ]. Porges et al [ 32 ] proposed a cut off of total lymphocyte count of <350 cells/mm 3  which captured 4 out of 6 cases with PCP and SLE, but only 1 of 20 patients with SLE unaffected by PCP. Information on CD4+ counts, which have been shown to be highly predictive of the risk of PCP in HIV infected individuals [ 38 ], is less well documented in AID patients. The issue was addressed by Mansharamani et al [ 19 ] who prospectively observed 171 patients in various risk categories for PCP, including 22 patients with active PCP. They found that patients who were at high risk of PCP had significantly lower CD4+ counts than patients at low risk. They noted that 91% of cases of PCP had CD4+ counts <300 cells/mm 3  at the time of diagnosis. Their findings are echoed by an increased risk of respiratory colonisation by P.jiroveci in HIV negative patients with CD4+ counts of <400 cells/ mm 3  [ 39 ]. Kadoya et al [ 37 ] in their study on the occurrence of PCP in 75 patients with inflammatory myopathy and SLE, noted a significant association between radiological interstitial pulmonary fibrosis (IPF) and the risk of PCP (8.8% IPF in non-PCP vs 100% IPF in PCP, p < 0.001). In contrast, PCP has only rarely been reported in idiopathic pulmonary fibrosis [ 15 ], indicating that more than systemic steroids and pulmonary fibrosis are required to put patients at excessive risk of PCP. Prevention Co-trimoxazole is commonly used for PCP prophylaxis in Wegener's granulomatosis when CD4+ counts are <300 cells/mm 3  [ 15 ] or even with normal counts in some centres [ 21 ]. This combination of antibiotics has been shown to be effective prophylaxis when used daily or thrice weekly at a dose of 960 mg in HIV positive patients [ 40 ]. Adverse effects occur in less than 20% of patients, usually manifesting as a rash, which resolves on temporary discontinuation and often does not recur on re-challenge [ 41 , 42 ]. Apart from Wegener's granulomatosis, identifying patients with AID who are at risk of PCP has proved a challenge, as the overall incidence is low. Nevertheless it remains an important issue, as AID patients contribute a considerable proportion of cases of PCP in HIV negative patients (up to 36%) and have a particularly poor prognosis, as discussed earlier. Any method used to select patients for prophylactic treatment needs to be assessed against set standards and have a high sensitivity and specificity. The standards should address the percentage of PCP cases captured by the selection criteria (ideally 100% but in practice >80%) and the risk of the condition in the selected group (which should be significant). In HIV patients who meet the criteria for PCP prophylaxis as set out by the US Public Health Service [ 43 ], the annual risk of PCP is 18% [ 38 ]. As the mortality from PCP in HIV negative patients is approximately double that of HIV-positive patients [ 14 - 18 , 27 ], we would suggest that an annual risk >9% of PCP would be sufficient to justify prophylaxis. In the study by Mansharamani et al, their proposed cut off of <300 CD4+ cells/mm 3  would capture 91% of cases of PCP in all HIV negative patients, but would also include 39–46% of patients on systemic steroids, most of whom would be unaffected by PCP. Administering prophylaxis to such large numbers of patients would unnecessarily expose patients to drug side-effects and potentially encourage drug resistance. However, analysis of their data reveals that the subgroup of patients with AID who developed PCP had CD4+ counts of <250 cells/mm 3  and six out of eight had counts <200 cells/mm 3  [ 19 ]. Given the laboratory costs, we would argue in favour of performing CD4+ counts after one month's immunosuppression only on patients who satisfy the following three screening criteria: • Steroid dosage >15 mg prednisolone or equivalent/day • >three months corticosteroid treatment proposed • total lymphocyte count <600 cells/mm 3 A CD4+ count <200 cells/mm 3  might then warrant the use of prophylactic co-trimoxazole, if the annual risk of PCP in these patients is greater than 9%. Most cases of PCP in patients with AID would be captured by these criteria, according to published series. Clearly, further prospective investigation is required to gather sufficient data to validate any selection method. To justify our proposed threshold for prophylaxis we would need to know the risk of PCP for patients on steroid-based immunosuppression for AID with CD4+ counts of <200 cells/mm 3 , information which is currently unavailable.
Discussion
Pneumocystis pneumonia in AID is unusual in the absence of steroid treatment. Corticosteroids have been recently administered in over 90% of cases in most series [ 14 , 17 , 18 , 22 ] and were the sole immunosuppressant in 17–28% of AID patients [ 18 , 22 ]. The median duration of treatment prior to the diagnosis of PCP is three to four months. Occurrence within a month of starting treatment is uncommon, with the exception of inflammatory myopathies [ 28 , 32 ]. Most cases have taken prednisolone in excess of 15 mg per day, or equivalent doses of corticosteroid. Notable is the profound inter-subject variation in response to standard steroid doses as measured by in vitro inhibition of lymphocyte proliferation [ 33 ], indicating that host factors are likely to have a significant, but as yet ill-defined role. Several mechanisms have been postulated to explain the role of steroids in promoting the development of P. jiroveci including CD4+ lymphocyte depletion and immune dysfunction [ 17 , 30 ]. Porges et al. found an association between the risk of PCP and the dose of prednisone used in SLE [ 32 ]. Similarly, Hellman et al. found an association between prednisolone dosage and risk of fatal opportunistic infection in SLE, the commonest cause of which was P. jiroveci [ 26 ]. However, other studies have failed to show an association between cumulative steroid dose and risk of PCP [ 34 ].A number of cytotoxic and other immunosuppressive agents commonly used in the treatment of AID are frequently associated with PCP, including cyclophosphamide, azathioprine, methotrexate and ciclosporin [ 14 ]. Cyclophosphamide is routinely used in the treatment of Wegener's granulomatosis and has transformed the previous one year survival figure of 20% [ 35 ] into the present eight year survival of 80% [ 36 ]. Godeau et al. [ 34 ] showed a significant association between cyclophosphamide cumulative dose and the risk of PCP. However, this was not an independent factor in multivariate analysis when lymphopenia was taken into account [ 19 ]. In one series involving 180 patients with Wegener's granulomatosis, no cases of PCP were identified amongst patients on cytotoxic therapy alone (although the authors did not specify the numbers involved), suggesting a permissive role for corticosteroids [ 30 ].Data on PCP associated with AID indicates lymphocytopenia (<1,000 cells/mm 3 ) is almost a prerequisite, with 91% of patients exhibiting a low lymphocyte count. Fifty percent of such PCP patients have total lymphocyte counts of <400 cells/mm 3  [ 22 ]. The pre-treatment lymphocyte count and lymphocyte counts during the first three months of immunosuppressive treatment in Wegener's granulomatosis have been shown to be predictive for PCP in multivariate analysis. A total lymphocyte count <600 cells/mm 3  was recorded in ten (83%) of 12 patients with PCP, but such a low lymphocyte count was recorded in 11 (34%) of 32 with Wegener's unaffected by PCP [ 34 ]. A similar association was found in a prospective study involving patients with SLE [ 37 ]. Porges et al [ 32 ] proposed a cut off of total lymphocyte count of <350 cells/mm 3  which captured 4 out of 6 cases with PCP and SLE, but only 1 of 20 patients with SLE unaffected by PCP.Information on CD4+ counts, which have been shown to be highly predictive of the risk of PCP in HIV infected individuals [ 38 ], is less well documented in AID patients. The issue was addressed by Mansharamani et al [ 19 ] who prospectively observed 171 patients in various risk categories for PCP, including 22 patients with active PCP. They found that patients who were at high risk of PCP had significantly lower CD4+ counts than patients at low risk. They noted that 91% of cases of PCP had CD4+ counts <300 cells/mm 3  at the time of diagnosis. Their findings are echoed by an increased risk of respiratory colonisation by P.jiroveci in HIV negative patients with CD4+ counts of <400 cells/ mm 3  [ 39 ].Kadoya et al [ 37 ] in their study on the occurrence of PCP in 75 patients with inflammatory myopathy and SLE, noted a significant association between radiological interstitial pulmonary fibrosis (IPF) and the risk of PCP (8.8% IPF in non-PCP vs 100% IPF in PCP, p < 0.001). In contrast, PCP has only rarely been reported in idiopathic pulmonary fibrosis [ 15 ], indicating that more than systemic steroids and pulmonary fibrosis are required to put patients at excessive risk of PCP.Prevention Co-trimoxazole is commonly used for PCP prophylaxis in Wegener's granulomatosis when CD4+ counts are <300 cells/mm 3  [ 15 ] or even with normal counts in some centres [ 21 ]. This combination of antibiotics has been shown to be effective prophylaxis when used daily or thrice weekly at a dose of 960 mg in HIV positive patients [ 40 ]. Adverse effects occur in less than 20% of patients, usually manifesting as a rash, which resolves on temporary discontinuation and often does not recur on re-challenge [ 41 , 42 ]. Apart from Wegener's granulomatosis, identifying patients with AID who are at risk of PCP has proved a challenge, as the overall incidence is low. Nevertheless it remains an important issue, as AID patients contribute a considerable proportion of cases of PCP in HIV negative patients (up to 36%) and have a particularly poor prognosis, as discussed earlier. Any method used to select patients for prophylactic treatment needs to be assessed against set standards and have a high sensitivity and specificity. The standards should address the percentage of PCP cases captured by the selection criteria (ideally 100% but in practice >80%) and the risk of the condition in the selected group (which should be significant). In HIV patients who meet the criteria for PCP prophylaxis as set out by the US Public Health Service [ 43 ], the annual risk of PCP is 18% [ 38 ]. As the mortality from PCP in HIV negative patients is approximately double that of HIV-positive patients [ 14 - 18 , 27 ], we would suggest that an annual risk >9% of PCP would be sufficient to justify prophylaxis. In the study by Mansharamani et al, their proposed cut off of <300 CD4+ cells/mm 3  would capture 91% of cases of PCP in all HIV negative patients, but would also include 39–46% of patients on systemic steroids, most of whom would be unaffected by PCP. Administering prophylaxis to such large numbers of patients would unnecessarily expose patients to drug side-effects and potentially encourage drug resistance. However, analysis of their data reveals that the subgroup of patients with AID who developed PCP had CD4+ counts of <250 cells/mm 3  and six out of eight had counts <200 cells/mm 3  [ 19 ]. Given the laboratory costs, we would argue in favour of performing CD4+ counts after one month's immunosuppression only on patients who satisfy the following three screening criteria: • Steroid dosage >15 mg prednisolone or equivalent/day • >three months corticosteroid treatment proposed • total lymphocyte count <600 cells/mm 3 A CD4+ count <200 cells/mm 3  might then warrant the use of prophylactic co-trimoxazole, if the annual risk of PCP in these patients is greater than 9%. Most cases of PCP in patients with AID would be captured by these criteria, according to published series. Clearly, further prospective investigation is required to gather sufficient data to validate any selection method. To justify our proposed threshold for prophylaxis we would need to know the risk of PCP for patients on steroid-based immunosuppression for AID with CD4+ counts of <200 cells/mm 3 , information which is currently unavailable.
Prevention
Co-trimoxazole is commonly used for PCP prophylaxis in Wegener's granulomatosis when CD4+ counts are <300 cells/mm 3  [ 15 ] or even with normal counts in some centres [ 21 ]. This combination of antibiotics has been shown to be effective prophylaxis when used daily or thrice weekly at a dose of 960 mg in HIV positive patients [ 40 ]. Adverse effects occur in less than 20% of patients, usually manifesting as a rash, which resolves on temporary discontinuation and often does not recur on re-challenge [ 41 , 42 ].Apart from Wegener's granulomatosis, identifying patients with AID who are at risk of PCP has proved a challenge, as the overall incidence is low. Nevertheless it remains an important issue, as AID patients contribute a considerable proportion of cases of PCP in HIV negative patients (up to 36%) and have a particularly poor prognosis, as discussed earlier.Any method used to select patients for prophylactic treatment needs to be assessed against set standards and have a high sensitivity and specificity. The standards should address the percentage of PCP cases captured by the selection criteria (ideally 100% but in practice >80%) and the risk of the condition in the selected group (which should be significant). In HIV patients who meet the criteria for PCP prophylaxis as set out by the US Public Health Service [ 43 ], the annual risk of PCP is 18% [ 38 ]. As the mortality from PCP in HIV negative patients is approximately double that of HIV-positive patients [ 14 - 18 , 27 ], we would suggest that an annual risk >9% of PCP would be sufficient to justify prophylaxis.In the study by Mansharamani et al, their proposed cut off of <300 CD4+ cells/mm 3  would capture 91% of cases of PCP in all HIV negative patients, but would also include 39–46% of patients on systemic steroids, most of whom would be unaffected by PCP. Administering prophylaxis to such large numbers of patients would unnecessarily expose patients to drug side-effects and potentially encourage drug resistance. However, analysis of their data reveals that the subgroup of patients with AID who developed PCP had CD4+ counts of <250 cells/mm 3  and six out of eight had counts <200 cells/mm 3  [ 19 ].Given the laboratory costs, we would argue in favour of performing CD4+ counts after one month's immunosuppression only on patients who satisfy the following three screening criteria:• Steroid dosage >15 mg prednisolone or equivalent/day• >three months corticosteroid treatment proposed• total lymphocyte count <600 cells/mm 3A CD4+ count <200 cells/mm 3  might then warrant the use of prophylactic co-trimoxazole, if the annual risk of PCP in these patients is greater than 9%. Most cases of PCP in patients with AID would be captured by these criteria, according to published series.Clearly, further prospective investigation is required to gather sufficient data to validate any selection method. To justify our proposed threshold for prophylaxis we would need to know the risk of PCP for patients on steroid-based immunosuppression for AID with CD4+ counts of <200 cells/mm 3 , information which is currently unavailable.Summary P. jiroveci infection in HIV negative patients presents more acutely and has a worse prognosis. The incidence of PCP in patients with AID is low, although these patients still represent a considerable proportion of all HIV negative cases. It is important to have a high index of suspicion of PCP when treating AID with steroid based immunosuppressive regimes, as early treatment could improve prognosis. The risk of infection is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Effective and relatively safe prophylaxis is available. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis. Further prospective trials are required to validate our proposed prevention strategy.
Summary
P. jiroveci infection in HIV negative patients presents more acutely and has a worse prognosis. The incidence of PCP in patients with AID is low, although these patients still represent a considerable proportion of all HIV negative cases. It is important to have a high index of suspicion of PCP when treating AID with steroid based immunosuppressive regimes, as early treatment could improve prognosis. The risk of infection is related to treatment with systemic steroid, ill-defined individual variation in steroid sensitivity and CD4+ lymphocyte count. Effective and relatively safe prophylaxis is available. Rather than opting for PCP prophylaxis on the basis of disease or treatment with cyclophosphamide, we argue the case for carrying out CD4+ lymphocyte counts on selected patients as a means of identifying individuals who are most likely to benefit from PCP prophylaxis. Further prospective trials are required to validate our proposed prevention strategy.Competing interests The authors declare that they have no competing interests.
Competing interests
The authors declare that they have no competing interests.Authors' contributions AJ Carmichael initiated the discussion, appraised results, lead departmental debates and helped revise the manuscript. ES carried out the literature search, presented at meetings and wrote the original manuscript. All authors read and approved the final manuscript.
Authors' contributions
AJ Carmichael initiated the discussion, appraised results, lead departmental debates and helped revise the manuscript. ES carried out the literature search, presented at meetings and wrote the original manuscript. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here: