Managing meningitis in people with HIV in resource-limited settings: a clinical review

This article originally appeared in HIV & AIDS treatment in practice, an email newsletter for healthcare workers and community-based organisations in resource-limited settings published by NAM between 2003 and 2014.
This article is more than 12 years old. Click here for more recent articles on this topic

Introduction

“Samual Nzala is a-24-year-old gentleman brought by his family to the clinic because of a severe headache. The family reports that he has "malaria." His temperature is 39.7 degrees, but no parasites were seen on his MP (malaria parasite) slide. When the nurse spoke with him, he was lying on the bed in clinic with his eyes shut looking very uncomfortable. He keeps his eyes shut to the light and moves as little as possible. He did not feel well yesterday, but was working earlier this week with no problems. He has never had headaches before except when he has malaria. This is the worst headache he has ever had.”

"His family says that he has had no recent head injuries, and the nurse cannot detect any focal problems (weakness or numbness in one part of the body) that might be evidence of a mass lesion in the brain, or signs of stroke. However, she finds he has a very stiff neck and is unable to flex his head forward.

She believes Samual most likely has some type of meningitis."

Adapted (with some details added) from Dr Gretchen Birbeck’s Where there is no neurologist — see resource section)

Glossary

meningitis

Inflammation of the outer lining of the brain. Potential causes include bacterial or viral infections.

 

palliative care

Palliative care improves quality of life by taking a holistic approach, addressing pain, physical symptoms, psychological, social and spiritual needs. It can be provided at any stage, not only at the end of life.

cryptococcosis

A type of fungal infection usually affecting the membrane around the brain, causing meningitis. It can also affect the lungs and chest.

central nervous system (CNS)

The brain and spinal cord. CNS side-effects refer to mood changes, anxiety, dizzyness, sleep disturbance, impact on mental health, etc.

retrospective study

A type of longitudinal study in which information is collected on what has previously happened to people - for example, by reviewing their medical notes or by interviewing them about past events. 

Meningitis, inflammation of the membranes covering the spinal cord or brain, is common in people with HIV — but may be caused by a variety of things. Samual’s symptoms: severe headache, fever, stiff neck, altered mental state or consciousness and sensitivity to light (photophobia) are hallmarks of meningitis—but not every symptom is always present and the clinical presentation may be non-specific. In people with HIV, meningitis may present with confusion only.  On the other hand, depending on the cause or individual, there may be other complaints as well that could complicate diagnosis.

Symptoms may vary with the cause, which is most commonly an infection of some sort (either bacterial, mycobacterial (TB), amoebic, fungal or viral (see below)), but could also be due to physical injury (head trauma), subarachnoid haemorrhages, autoimmune conditions, cancers, or exposure to certain chemicals (Joynt). Some of these symptoms may not actually be due to involvement of the brain at all – for instance, sinusitis can cause a headache, severe dehydration due to malaria may cause altered mental state, and a stiff neck may occasionally be a feature of bacterial pneumonia.

This article will deal chiefly with the infections causing meningitis to which people with HIV may be more vulnerable —with a particular focus on cryptococcal, TB and pneumococcal meningitis.

Even with the roll-out of antiretroviral therapy (ART), being on the alert for meningitis is very important, because it may be the first illness that a person develops and is very dangerous.

Symptoms suggestive of meningitis must be treated as a medical emergency, since clinical deterioration can be very rapid and lead to death. Even when the initial presentation is initially subacute, as can be the case with cryptococcal meningitis, the consequences of delay are so grave that virtually any severe headache with a recent onset in a person with HIV may warrant a closer examination (Hakim).

In either case, prompt and appropriate attention can improve survival and reduce the risk of serious long-term complications.

But often in resource limited settings, diagnosing meningitis in a very ill person (or getting the person with meningitis to a place where he or she can be diagnosed), and providing effective care and treatment can present a number of difficult challenges. And even when a case is diagnosed and treated, few programmes adequately address how to manage the long-term consequences of meningitis in the children and adults who survive the condition.

Prevalence of meningitis in resource-limited settings

Diagnosis of meningitis

Treatment of the infectious cause of meningitis

Treatment for the identifiable (or suspected) cause of meningitis should be the first priority in each patient with meningitis and HIV. However, good long-term outcomes can only be achieved by also eventually putting people on ART (and perhaps other preventive therapy — see prevention below), and by managing the patient’s increased intracranial pressure (through repeated lumbar punctures, appropriate analgesics for pain and other needs that may arise as a complication of meningitis (see caring for the patient below). However, the introduction of ART after a serious neurological infection does raise the potential for IRIS to develop — and as Dr Collin’s case suggests, many clinicians are unsure when is the best time to initiate ART in someone who has had meningitis (see below).

Reducing suffering in a person with meningitis and managing its long-term consequences

One thing that literature sometimes neglects to mention is the intense suffering that people with meningitis go through — such as the screaming patient that Dr Collins was caring for.

As frightening as lumbar punctures may sound to some, in the case of cryptococcal meningitis, they do provide real pain relief since much of the pain is due to high pressure around the brain. In fact, “simply relieving the pressure is the most potent and immediate form of pain relief,” said Dr. Venter.

But appropriate pain medication must be prescribed as well, commensurate to the level of pain that the individual is enduring (See the WHO analgesic ladder in the Resources section). (NSAIDS however should be avoided in patients on amphotericin B due to a risk of kidney toxicity).

In addition, A clinical guide to supportive and palliative care for HIV/AIDS in sub-Saharan Africa (see Resources section) recommends “other measures such as being in a quiet, dark room, having a cool cloth over the eyes, and having the neck massaged may be helpful.” It also stresses that adopting a palliative care approach also extends to addressing psychosocial issues related to the illness.

“Consider the implications of the person’s condition for his or her ability to continue to work. In addition, there have been unfortunate incidences of patients with dementia or delirium being thrown out of their homes or of being locked up in a small shed.”

This would likely result in the rapid death of someone with meningitis.

In addition, meningitis can also result in permanent brain damage, hearing loss, blindness, partial paralysis or learning disabilities in survivors — especially if diagnosis and treatment are delayed.  Health systems aren’t prepared to manage such individuals, as the following case submitted by Dr Natalya Dinat, Director of Wits Palliative Care, at the University of Witwatersrand illustrates:

Prevention of meningitis

Given such challenges, as the old adage goes, prevention would certainly be better than a cure.

“Approaches to reducing the incidence include the deployment of effective antiretroviral therapy in areas where HIV co-infection is common, vaccination, and prophylactic antibiotic therapy,” wrote Scarborough and Njalale from Malawi.

  • Vaccination for the major causes of bacterial pneumonia is recommended in people with HIV, even though the protection offered may not be as great as in the general population, particularly in those with lower CD4 cell counts (Spach). However, data from one study with the 23-valent pneumococcal polysaccharide vaccine in Africa found that vaccination was associated with an increased risk of pneumoccoccal disease (French). However, recent studies have shown PCV-7 (7-serotype conjugate pneumococcal vaccine) to be safe and efficacious when used in children infected with HIV, and WHO now recommends that countries with a high prevalence of HIV prioritise the introduction of this vaccine (http://www.who.int/entity/wer/2007/wer8212.pdf). In addition, good national vaccination policies could also reduce the overall burden of bacterial pneumonia through “the herd effect.” (Klugman)
  • Cotrimoxazole prophylaxis has been shown to reduce the frequency of bacterial infections — even in Zambia, where there is a high level of background antibiotic resistance (Mulenga http://www.aidsmap.com/en/news/DFC83829-056C-4C24-94FE-BAB37FA7BDE0.asp).
  • Isoniazid preventive therapy (IPT) reduces the incidence of TB and making it a part of the essential package of care offered to people with HIV could potentially reduce the risk of TB meningitis as well.
  • Fluconazole prophylaxis: The use of prophylaxis to prevent cryptococcal meningitis and other infections is more controversial. Although several randomised studies have shown that fluconazole and itraconazole reduces the incidence of cryptococcal disease in people with advanced HIV disease, and one study even demonstrated a survival benefit, none of these studies have been conducted in sub-Saharan Africa (Chang, Chetchotisakd). In addition, concerns have been raised about the potential drug interactions (as with nevirapine), the potential for teratogenicity, and the risk of developing fluconazole-resistant thrush infections.

So WHO’s draft guidelines on the Essential Prevention and Care Interventions for PLHIVs, includes a recommendation to consider fluconazole prophylaxis in areas where cryptococcal disease is common for severely immunocompromised people with HIV (WHO clinical stage 4 or CD4 < 100 cells) but the level of recommendation is ‘optional.’

The SAHCS guidelines stress that the priority should rather be to get people with such low CD4 cell counts on ART as soon as possible.

“ART is the most effective intervention to treat AIDS, and is the most potent mechanism to prevent both primary and secondary recurrences of cryptococcosis.” However, it concedes that “primary prevention… with fluconazole may have a limited role in patients with CD4 counts below 100 cells where delays in access to ART are anticipated.”

Unfortunately, such delays are common in South Africa… and can have serious consequences, as the final case from Dr Dinat illustrates.

Resources for palliative and supportive care for people with disabilities

References (in order of appearance in the review)

Joynt RJ, ed. Clinical neurology, rev. Philadelphia: JB Lippincott, Chapter 24, 1993.

Hakim J. Epidemiology of HIV CNS disease in sub-Saharan Africa. Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, Venice, Italy, 2007.

Schutte CM The impact of HIV on meningitis as seen at a South African Academic Hospital (1994 to 1998). Infection; 28(1):3-7, 2000.

McCarthy KM et al. Population-based surveillance for cryptococcosis in

an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS, 20:2199–2206, 2006.

Hakim JG et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS;14(10):1401-7, 2000.

Bogaerts J et al. AIDS-associated cryptococcal meningitis in Rwanda (1983–1992): epidemiologic and diagnostic features. J Infect; 39:32–37, 1999.

Békondi C et al. Primary and opportunistic pathogens associated with meningitis in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus. Int J Infect Dis. 10(5):387-95, 2006.

Jowi JO East. Clinical and laboratory characteristics of hospitalised patients with neurological manifestations of HIV/AIDS at the Nairobi hospital. Afr Med J;84(2):67-76, 2007.

Matee MI, Matre R.  Pathogenic isolates in meningitis patients in Dar Es Salaam, Tanzania. East Afr Med J. 78(9):458-60, 2001

Chariyalertsak et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis; 34(2):277-84, 2002.

Helbok R et al. Chronic meningitis in Thailand. Clinical characteristics, laboratory data and outcome in patients with specific reference to tuberculosis and cryptococcosis. Neuroepidemiology;26(1):37-44, 2006.

Subsai K et al. Neurological complications in AIDS patients: the 1-year retrospective study in Chiang Mai University, Thailand. Eur J Neurol; 11:755–9, 2004.

Ghate M. Epidemiology of HIV CNS disease in India. Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, Venice, Italy, 2007.

Pallangyo K et al. High HIV seroprevalence and increased HIV-associated mortality among hospitalized patients with deep bacterial infections in Dar es Salaam, Tanzania. AIDS;6(9):971-6, 1992.

Cecchini D Tuberculous meningitis in HIV-infected patients: drug susceptibility and clinical outcome. AIDS;21(3):373-4, 2007.

Thwaites GE et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis;192(12):2134-41, 2005.

G.E. Thwaites. Central Nervous System Tuberculosis. Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, Venice, Italy, 2007.

M.G. Croda et al. Associated factors to in-hospital mortality and long-term

survival in Brazilian HIV-infected patients with tuberculous meningitis in the HAART era. Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, Venice, Italy, 2007.

Maher D, Mwandumba H.  Cryptococcal meningitis in Lilongwe and Blantyre, Malawi. J Infect;28(1):59-64, 1994.

Soumaré M et al. Epidemiological, clinical, etiological features of neuromeningeal diseases at the Fann Hospital Infectious Diseases Clinic, Dakar (Senegal). Med Mal Infect;35(7-8):383-9, 2005.

Mwaba P et al Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J;77(914):769-73, 2001.

Moosa MYS, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features,laboratory findings and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients. Clin Infect Dis; 24:131–134, 1997.

Bergemann A, Karstaedt AS. The spectrum of meningitis in a population with high prevalence of HIV disease. QJM;89(7):499-504, 1996.

Scarborough M, Njalale Y.    Bacterial meningitis in a high HIV prevalence setting in sub-Saharan Africa--challenges to a better outcome. Trop Doct; 34(4):203-5, 2004.

de Almeida SM et al. Acute bacterial meningitis in HIV, patients in southern Brazil: Curitiba, Paraná, Brazil. Arq Neuropsiquiatr;65(2A):273-8, 2007.

Almirante B et al. Favorable prognosis of purulent meningitis in patients infected with human immunodeficiency virus. Clin Infect Dis;27:176-180, 1998.

Molyneux EM et al. The effect of HIV infection on paediatric bacterial meningitis in Blantyre, Malawi. Arch. Dis. Child.; 88;1112-1118, 2003.

Gordon SB et al. Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe, and seasonal. Clin Infect Dis;31(1):53-7, 2000.

Janoff EN et al. Pneumococcal disease during HIV infection: epidemiologic, clinical, and immunologic perspectives. Ann Intern Med;117:314–24, 1992.

Simon, RP. Neurosyphilis. Arch Neurol;42: 606-613, 1985

Carmo RA et al. Syphilitic meningitis in HIV-patients with meningeal syndrome: report of two cases and review. Braz J Infect Dis;5(5):280-7, 2001.

Johns DR et al Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med;316(25):1569-72, 1987.

Padayatchi N et al. Multidrug-resistant tuberculous meningitis in children in Durban, South Africa. Pediatr Infect Dis J;25(2):147-50, 2006.

Wilson D et al (eds). South African Handbook of HIV Medicine. Cape Town, Oxford University Press Southern Africa, Chapter 19, 2002.

Karstaedt AS et al. Tuberculous meningitis in South African urban adults. QJM;91(11):743-7, 1998.

French N et al. 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected Ugandan adults: double-blind, randomised and placebo controlled trial. The Lancet 355: 2106-2111, 2000.

Gluckman SJ. Cryptococcal infections in patients with AIDS. Bostwana International HIV Conference. Gaborone, 2006.

Nowak DA et al. A retrospective clinical, laboratory and outcome analysis in 43 cases of acute aseptic meningitis. Eur J Neurol;10(3):271-80, 2003.

WHO. Laboratory manual for the diagnosis of meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae, Geneva, Switzerland, 1997.

van der Horst CM et al. Treatment of cryptococcal meningitis associated with acquired immunodeficiency syndrome. N Engl J Med; 337:15–21, 1997.

Graybill JR et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis; 30: 47–54, 2000.

McCarthy K and Meintjes G, Convenors. Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients The Southern African Journal of HIV Medicine, Spring 2008.

CDC (Centers for Disease Control and Prevention). Guidelines for treatment of sexually transmitted diseases. MMWR 47:1-116, 1998.

Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician;68(2):283-90, 2003.

Sungkanuparph S.  Cryptococcosis of the central nervous system: classical and immune-reconstitution disease. Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, Venice, Italy, 2007.

Thwaites GE et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med; 351:1741–51, 2004.

WHO and UNAIDS: Management of sexually transmitted diseases. WHO/GPA/TEM/94/1 Rev 1, Geneva, 1997.

Saag MS et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30:710–8.

Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomized trial. Lancet; 363:1764–7, 2004.

Lortholary O. Management of cryptococcal meningitis in AIDS: the need for specific studies in developing countries. Clinical Infectious Diseases 2007; 45:81–3.

Schaars CF et al. Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole. BMC Infectious Diseases; 6: 118, 2006.

Bicanic T. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clinical Infectious Diseases; 45:76–80, 2007.

Jongwutiwes, U et al. Impact of antiretroviral therapy on the relapse of cryptococcosis and survival of HIV-infected patients with cryptococcal infection. Current HIV Research, 5(3),355-360(6), 2007.

Sungkanuparph S et al.  Opportunistic infections after the initiation of highly active antiretroviral therapy in advanced AIDS patients in an area with a high prevalence of tuberculosis. AIDS. 17(14):2129-2131, September 26, 2003.

Lawn SD et al. Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS 2005; 19:2050–2.

Pitt J et al. The effect of fluconazole on nevirapine pharmacokinetics. Int Conf AIDS; 15: abstract no. WeOrB1239, 2004.

Manosuthi W et al. Safety and tolerability of nevirapine-based antiretroviral therapy in HIV-infected patients receiving fluconazole for cryptococcal prophylaxis: a retrospective cohort study. BMC Infectious Diseases 5:67, 2005.

Manosuthi W et al. Plasma nevirapine levels, adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole BMC Infectious Diseases 7:14, 2007.

Mulenga V et al. Effect of cotrimoxazole on causes of death, hospital admissions and antibiotic use in HIV-infected children. AIDS 21: 77-84, 2007.

Chang L et al. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev (3):CD004773, 2005.

Chetchotisakd P et al. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med;5(3):140-3, 2004.

Advisors

Contributing Clinical Advisers

Dr Doug Wilson,

Edendale Hospital,

KwaZulu Natal, South Africa

Dr Francois Venter

Reproductive Health and HIV Research Unit

University of the Witwatersrand, Johannesburg, South Africa

Dr Graeme Meintjes

GF Jooste Hospital

Cape Town, South Africa

Dr. Somnuek Sungkanuparph

Ramathibodi Hospital

Mahidol University, Bangkok, Thailand

Dr. Gretchen Birbeck

Michigan State University

Principal Investigator: for the

Rural ART adherence in Zambia (RAAZ) study

Contributing Palliative Care Advisers

Dr. Joan Marston

Paediatric Palliative Care Manager for Hospice Palliative Care

Association of South Africa

Chair of the International Children’s Palliative Care Network in South Africa

Dr. Natalya Dinat

Director of Wits Palliative Care,

University of Witwatersrand,

Chris Hani Baragwanath Hospital

Johannesburg, South Africa

Dr Karilyn Collins

Muheza Hospice Care

Teule Hospital, Muheza Tanzania