Bacterial meningitis in HIV-infected patients : Case re ports and review of the literature

Meningitis is not an uncommon complication of the acquired immune deficiency syndrome. Purulent meningitis is not a well recognized infection in human immunodeficiency virus (HIV) positive patients. Three cases of bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis and Listeria monocytogenes are presented. These cases illustrate that common community organisms may present in HIV positive patients. An acquired B cell defect may predispose to bacterial infections responsible for meningitis in HIV-infected patients.

A 23-year-old heterosexual Caucasian male had been diagnosed with severe hemophilia A at six months of age.Past medical history included an intracranial bleed at three years of age.accompanied by behavioral changes .He was tested and found to be positive for HIV four years prior to admission and his general state of health was good prior to admission.The patient was brought to emergency after being found confused, shivering and unable to respond appropriately.He had complained of a headache for three days prior to admission.There was no recent weight loss over the preceding months, nor was there a recent episode of hemarthrosis.There was no history of intravenous drug use but the patient had ab used cocaine.He had received transfusions of factor VJII for numerous episodes of small hemarthroses in the late 1970s and early 1980s.
On examination the patient was delirious and appeared toxic.His temperature was 39.8°C, pulse 108 beats/min.and respirations 48/m.in.Blood pressure was 156/98 mmHg.The patient was unable to respond to verbal commands.His eyes opened spontaneously and they were conjugately deviated to the right.He responded to pain and moved all limbs spontaneously.He appeared irritable.There was nuchal rigidity and positive Kemig's and Brudzinskfs signs.There was no petechial or papular rash.
Computed tomography (CT) scan of the head on initial examination revealed a low density lesion at the left middle cranial fossa consistent with an arachnoid cyst.No enhancing mass lesion or hemorrhage was identified.
White blood cell count was 13 .3x10 9/L with 80% n eutrophils.4% lymphocytes and 8% monocytes.Prothrombin time was 13.4 s, partial thromboplastin time 78.6 s, and factor Vllllevel was 1%.The patient was given dexamethasone 10 mg and phenytoin 1 g intravenously.Factor Vlll (6000 units) was given prior to lumbar puncture.At the time of the lumbar puncture, 20% mannitol was initiated.The patient's cerebrospinal fluid was cloudy, with protein 1.5 g/L and glucose 0.8 mmol/L (6.4% of serum value).Cerebrospinal fluid white cell counts were not available due to the presence of clots.but the differential cell counts were 85% neutrophils and 15% lymphocytes.
The patient was treated with intravenous penicillin G 24 million units per day.The cerebrospinal fluid and blood grew Streptococcus pneumoniae sensitive to penicillin .His recovery was complicated by respiratory arrest requiring intubation and mechanical venWation , and left lower lobe pneumonia.Recovery was further complicated by bilateral sensorineural deafness and neurogenic urinary retention remaining after successful treatment of meningitis and pneumonia.

CASE TWO
A 24-year-old homosexual Caucasian male diagnosed as HIV infected t\vo years prior to admission presented to emergency with a painful left ankle.The patient appeared awake.alert and oriented.He complained of fever and chills.His history was initially negative for ankle trauma or swelling, rash, headache.photophobia or neck stiffness.Blood cultures were drawn and the patient left the emergency room.Cul-tures were positive for Gram-negative diplococci.The patient was recalled to emergency and was found to have n eck stiffness.He subsequently became obtunded.There was no recent histmy of weight loss .He had no history of intravenous drug abuse or transfusions.There was a history of penicillin allergy.
On exan1.ination the patient was obtunded but appeared well nourished.He was photophobic and agitated by light.He was unable to respond to verbal commands.His eyes opened spontaneously but did not fixate on any object.His temperature was 38.4°C, pulse 94 beats/min, and respirations 18/min.Blood pressure was 130/70 mmHg.He responded to pain with withdrawal.Fundoscopic examination was negative for papilledema.Kernig's sign was positive.There was bilateral cervical lymphadenopathy and nuchal rigidity.A petechial rash was present over the abdomen.The left ankle appeared unremarkable.CT scan of the head was normal, as was a chest radiograph.
White blood cell count was 13.4x10 9 /L witl1 87% neutrophils, 6.5% lymphocytes and 5.6% monocytes.Platelet count was 142x10 9 /L and eryilirocyte sedimentation rate 64 mm/h.Prothrombin time was 14.4 s and partial thromboplastin time 35.8 s.Blood cultures were positive for Neisseria meningitidis.The CD4/CD8 (TJ,/Tsl ratio was 0.34 and the CD4+ cell count was 20% or 282xl0 6 /L.The patient was treated witl1 intravenous chloramphenicol and recovery was uncomplicated.

CASE THREE
A 29-year-old male with seroconversion for HIV four years earlier was admitted complaining of crampy abdominal pain about the epigastrium radiating to his left flank The pain began two days prior to admission and was worsened by movement and eating.Nausea was an associated finding.There was no vomiting.diarrhea or melena on admission.The patient discontinued his medication of clofazimine, cyclosporine, ethionamide and zidovudine with tl1e onset of pain.He also complained of wealmess, increasing cough and dyspnea .Allergies included sulpha and penicillin, manifested by a rash.Past history included pneumocystis pneumonia and disseminated Mycobacterium avium intracellulare infections .
On examination tl1e patient was nonnotensive.afebrile and had normal pulse and respiratory rates.Head and neck examination was unremarkable on admission.The patient demonstrated abdominal left lower quadrant pain upon flexion of the hips .The chest was clear to auscultation.Abdominal examination revealed a tender liver edge with a total span of 12 em in the right midclavicular line.Bowel sounds were normal.He was tender upon deep palpation in the para-umbilical region, and a definable tender mass was palpated over the left flank.
Abdominal three views revealed localized ileus with nondistended small bowel and a few air-fluid levels .Abdominal ultrasound demonstrated an ill defined amorphous mass in the left para-aortic region measuring 9 em in diameter consistent witl1 enlarged lymph nodes.White blood cell count was 7 .8x10 9/L witl1 82% neutrophils.16% lymphocytes and 2% monocytes.
Hemoglobin was 72 g/L and p latelet count 1.23x 10 9 I L.
Serum electrolytes revealed borderline hyponatremia at 132 mmol/L upon admission which later decreased to 113 mmol/L during the course of the illness.The CD4/CD8 (Th/Ts) ratio was 0.08, and the CD4+ cell count was 6% or 61xl0 6 /L.
The patient deteriorated after admission complaining of headache and vomiting.He became pyrexial.and antibiotics beginning with tobramycin and clindan1ycin were started after blood cultures were drawn.Blood cultures yielded Gram-positive bacilli.Lumbar puncture was performed with an opening pressure of 25 cmHzO.Cloudy cerebrospinal fl uid was obtained wiU1 glucose 0.4 mmol/L (serum glucose of 5.6 mmol/L).and a white cell count of 252x10 6 /L.The differential cerebrospinal fluid cell counts were 88% neulrophils and 11 % lymphocytes.
Blood cultures and cerebrospinal fluid grew Listeria monocytogenes.The patient had a negative skin test to penicillin and was started on intravenous ampicillin and gentan1icin .His mental status deteriorated initially and then returned to normal with gradual correction of serum sodium.The patient com pleted 10 days of antibiotics but developed a generalized pruritic erythematous rash after stopping ampicillin.He was treated satisfactorily with antihistamines.

LITE RATURE SEARC H
A literature search was carried out of on-line MEDLINE and AIDSLINE databases by computer search.references from abstracts from the Vth international conference on AIDS.textbooks and journals.Key words included "bacterial infections•.•meningitis• and 'HIV'.The general literature on bactetial meningitis and HIV was also reviewed.

DISCUSSION
Causes of meningitis in seropositive HIV patients include cryptococcus.HIV.tuberculos is .syphilis, coccidioidomycosis and lymphoma (7.8).A search of U1e English literature found only two reported cases of pneumococcal meningitis in HIV-infected patients (6. 1 0) .Simberkoff and associates (6)

have reported U1at
Strep pneumoniae infection is very common among patients \vith AIDS .Bacterernic Strep pneumoniae disease occurs more frequently in HIV-infected patients without symptoms of AIDS or AIDS-related comp lex lhan in symptomatic cases: consequently.pneumococcal bacteremia is postulated to be an important first indicator of HIV infection (11).

Bacterial meningitis in HIV infection
Strep pneumoniae accounts for 10 to 15% of all cases of reported bacterial meningitis in the United States.Estimates of incidence fro m commun ity-based stu dies range from 1.2 to 2.8 cases per 100,000 persons per year in the United States .It is seen p rimarily in young ch ildren.particu larly children younger than h'IO years of age.and it is the most common cause of bacterial meningitis in adults over 60 years of age ( 12).
Meningococcal meningitis accounts for about 20 to 30% of all reported cases of bacterial meningitis in U1e United States.The overall incidence estimated from community-based studies ranges from 0 .18 to 9.2 cases per 100,000 persons per year (12).L monocytogenes is an infrequent cause of meningitis-approximately 2% of all reported cases in U1e Centers for Disease Control study from 1978-8 1 (13).The estimated incidence in this population was 0.04 cases per 100.000persons per year (12).Listetial meningitis occurs in neonates and in adult populations wilh immunosuppression.alcoholism and diabetes mellitus.L monocytogenes is also a common cause of bacterial meningitis in renal transplant patients .
It was not unexpected in U1e present study to find L monocytogenes in AIDS patients, but it is surprising U1at more cases are not reported.The incidence of listeriosis in patients with AIDS or at risk for HIV has increased compared to the non -HIV and nonrisk groups in New York City from 1981 to 1988.Listeria!meningitis in New York City was identified in U1ree of 11 patients (27%) with listeriosis who were HIV-infected or at risk for HIV (14).A recent review of 20 cases of listeriosis in HIV-infected patients described nine patients wiU1 meningitis and one with brain abscess (15) .There was no reported case of neisseria meningitis in HIV-infected patients.although instances of N meningitidis bacteremia have been reported (16).
Recent studies report the importance of bacterial infections particularly in the pediatric population .A prospective study in African children found that bacteremia was a predictor of HIV infection.wiU1 44% seropositivity in U1e bacteremic group versus 19% seropositivity in the culture negative group (17) .Group B streptococcal meningitis has been identified in h'lo of 200 (1.0%)HIV-infected Ame1ican children diagnosed atlhe University of Maryland and U1e New York University Medical Center.wiU1 infection occurring beyond the usual age of onset in U1ese ch ildren (18).
Severe meningitis from encapsulated organisms such as Sirep pneumoniae.N meningitidis and Haemophilus injluenzae could result from a lack of activation of B cells by capsular antigens in patients with AIDS (1.2).Investigations of B cell function in patients wilh AIDS have shown significantly lower antibody levels to polysaccharide and protein anti<Jens after immunization with pneumococcal polysaccharide and protein antigens (l).A possible mechanism of meningitis in HIV-infected patients could relate to abnormalities in intrinsic B cell physiology and a lack of CD4+ T h elper cells in initiating specific antibody production.In affected a dults.serum levels of IgG , lgA and IgD have been reported to be incr eased whereas IgM is relatively normal (2 -5) .
The primary differential diagnosis considered by clinicians in HIV-infected patients presenting with an altered mental state includes cryptococcal m eningitis .central nervous system toxoplasmosis.central n ervo us system lymphoma.neurosyphilis.cytomegalovirus encephalitis , progressive multifocal leukoencephalopathy. and HIV encephalopathy.However, bacterial meningitis may be more prevalent in HIV-infected patients than previously realized .It is very possible that there is under-reporting of bacterial meningitis in HIV patients as these microorganisms are well recognized causes of meningitis even in h ealthy adults within the same age group.It is also possible that the cases of pneumococcal and meningococcal meningitis occulTing in HIV patients occurred by chance with no increased predisposition due to HIV status .The occurrence of pneumococcal or H influenzae sepsis is not reportable which makes estim a tion of the expected incidence rates in HIV-infected groups unreliable.
The occurrence of the three present cases of bacterial m eningitis in HIV-infected patients at one institution over one year suggests that bacterial meningitis may be more prevalent in HIV-infected patients than previously realized.Prospective studies of the incidence of bacterial meningitis are n eeded for a larger population in both HIV and non-HIV groups to obtain an accurate estimate of disease incidence and to control for other unrecognized factors affecting this hypothesis.However, if a higher incidence of bacterial m eningitis in the HIV-infected group is demonstrated, a higher suspicion of bacterial meningitis will be required in HIV-infected patients after cryptococcal meningitis is ruled out.