Annual Report

### **Tuberculosis**

Department of State

July 2001 through June 2002

Joe P. Bryan, MD, FACP

**Introduction.**

Tuberculosis is one of the major causes of death worldwide, perhaps the
second leading infectious cause of death among adults worldwide. An
estimated 2 million persons die of TB annually and 2 billion --
one-third of the world's population- are infected with TB (1). Exposure
to tuberculosis is an occupational hazard for those who work in areas
where tuberculosis is endemic. In the United States, rates of
tuberculosis declined to all time lows in 2001. This follows increased
rates associated with TB in HIV-infected persons during the decade of
1980.

In 1989, the United States embarked on a bold new plan to eliminate TB
from the United States by the year 2010 (2). The cornerstones of this
plan include: aggressive case finding and treatment of active cases,
evaluation of contacts of active cases, and treatment of the large
reservoir of persons with latent (inactive, non-infectious)
tuberculosis. This strategy includes treatment of all persons who are
newly infected with TB as manifest by a new skin test conversion within
the last two years, persons with conditions in which risk of activation
of tuberculosis is increased (HIV, immunosuppression, silicosis,
diabetes, etc.), recent immigrants to the US (because their rates of
infection mirror those of their country of origin for the first five
years in the US), and other persons with latent TB.

Within the Department of State, an ongoing program detects and treats
new cases and offers treatment for latent TB. The Department provides
medications without charge to Foreign Service Officers and eligible
family members who become infected. For Latent TB, Isoniazid (INH) has
been used since the 1950's. The current regimen consists of daily dosing
for 9 months (270 doses given with 360 days). More recently, studies in
persons infected with HIV have suggested Rifampin daily for 4 months is
an effective preventive therapy. The combination of Rifampin and
pyrazinamide for 2 months was recommend in 2000 (3) though this regimen
was withdrawn in August, 2001 because of unexpected toxicity (4, 5).

This report describes the experience with tuberculosis in the Department
of State (DOS) during the time period June 1, 2001 through July 30,
2002.

**Methods**

Tuberculosis, either active or latent is one of the infectious diseases
that is reported to M/MED each month on the Monthly Health Unit Report.
Active and latent TB cases are reported on a one-page report forms that
includes demographic information, health information relative to TB and
treatment recommendations. Health units are instructed to offer TB skin
testing annually with the Mantoux test Purified Protein Derivative (PPD)
0.1 ml intradermally in areas where TB is endemic. On the report for
active TB, detailed information on the *Mycobacterium tuberculosis*
isolates including sensitivities to usual anti-tuberculosis medications
are requested. Persons undergoing therapy for latent or active TB are
requested for complete a daily medication and side effect log to assist
in clinical monitoring and verification of treatment. Evaluation of
these reports is the basis for this report. In the summer of 2002, we
(Ken , a college student working in the department) reviewed the number
of monthly medication reports submitted and sent letters of inquiry to
persons from whom no monthly medication reports had been received.
Finally, we developed a certificate of completion for persons who
completed therapy for latent TB. We mailed a copy to the patient and
placed on copy in the medical record.

## Results

Latent TB:

This report covers the period July 2001 through June 2002. During this
period, 307 persons with latent TB and three persons with suspected or
confirmed active TB were reported to the Office of Medical Services. Of
the latent cases, one-hundred and seventy-five (57%) of cases were
identified in Washington in the Exam Clinic and the others were reported
from post health units. There were 132 male and 175 female patients.
Figure 1 shows the age distribution, the number of persons known to have
developed a positive TB skin test within the past two years, the number
of persons known to have latent TB for more than 2 years, and for those
for whom the duration of infection is unknown. The groups with the
highest proportion of known new conversions include children 0-19 years
and those 40-49 years. A large group of person 30-39 have latent TB of
unknown duration.

The rate of TB skin test conversion can be estimated from the monthly
statistical reports. For January through June 2002, the number of new
cases of latent TB reported by Posts was 41 new conversions during the
first quarter of 2002 and 52 during the second quarter of 2002. A range
of 0.04 to 0.08 per 100 persons at post per month is calculated
(4-8/10,000 persons per month). This is a substantial number of
infections. However, a rate calculated on the number of persons actually
tested would certainly be higher.

At least 163 of 307 (54%) of the cases of latent TB were found in
persons born outside the United States. Females born outside the US
comprise the largest group (104 \[35%\] of 307 patients).

Treatment regimens.

  ----------------------- ----------------------- -----------------------
  Regimen                 Number of persons       Percent

  INH                     184                     60

  Rifampin                16                      5

  Rifampin plus PZA       48                      16

  Deferred                20                      7

  Pre-employment          17                      6

  Information incomplete  22                      6

  Total                   307                     100
  ----------------------- ----------------------- -----------------------

Based on US Public Health Service Recommendations, approximately 48
patients were prescribed rifampin plus pyrazinamide for 2 months.
However, after a number of reports of adverse events associated with the
combination, the USPHS recommended on August 31, 2001 that the
combination not be prescribed. The recommendation suggested changing
patients to four months of rifampin alone or to INH alone (5). The
Office of Medical Services made extensive efforts to contact the 48
persons in late August, 2001. Twelve patients reported completion of the
treatment regimen and 3 were tolerating it well, 17 had not started, 11
reported side effects including one person who was hospitalized with
hepatitis. We were unable to contact 5 persons.

Completion of course. Of persons who began therapy between June 1 and
October 1, 2001 (had adequate time to complete therapy for 9 months),
verification of completion of therapy has been obtained for 54 (35%) or
153 persons. Some decided not to take the medication but for the
majority, no information is available.

Active TB: During this period, we received information on one confirmed
and two suspected cases of active TB. The confirmed case is a 47
year-old American-born woman in Guatemala City who developed symptoms of
cough with hemoptysis on Feb 8, 2002. Her PPD was recorded as negative
in June of 2001. Acid Fast Bacilli were found on sputum exam and
*Mycobacteria tuberculosis* grew on cultures that were sent to Miami,
FL. The patient was treated with four drugs for two months and two drugs
for an additional four months. The organism was susceptible to
streptomycin, IHN, rifampin, ethambutol and PZA. Contact evaluation of
family, maid, friend and language tutor revealed no additional cases of
active TB on initial evaluation, but 3 month follow-up is unknown. The
patient had extensive social contacts including a cocktail party with 60
in attendance and a father /daughter dance with approximately 200 in
attendance as well as volunteer experience at school, tennis lessons,
health club, hair salon etc. School officials where the woman
occasionally volunteered (non-classroom) were notified and subsequently
notified parents of children to encourage annual TB skin testing.

There were two suspected cases. The first is a 17 year-old female in
Bangkok who received treatment for latent TB in 1996 with INH for 6
months by Dr. Smirniotopoulous based on a PPD of 40 mm after living in
Bangkok. She lived in Burma from 1996-99. Back in Thailand, she
developed symptoms suggestive of TB with CXR changes in 2001. A
bronchoscopy did not reveal a diagnosis. However, the patient was
treated with four drugs for two months and four drugs 4 months with
clinical improvement.

The other suspected case is a 55 year old male who was stationed in
Singapore?. On a clearance exam, his CXR revealed bilateral cavitary
lesions. The patient is a heavy smoker. A bronchoscopy done in southeast
Asia was non-diagnostic. A PPD at that time was negative. The patient
was treated with four drugs. Subsequently, he returned to the US. A PPD
done in the U.S. at the Foreign Service Institute was reportedly
reactive at 20 mm on July 13, 2001. The patient saw a pulmonary
specialist at another government treatment facility in the Washington
area. The specialist recommended, based on erroneous information that
the TB skin test was negative, that TB medications be stopped and that
follow CT scans be done. The patient moved to Europe.

The monthly statistical reports received from posts indicate 8 cases of
active TB between January and July 2002. This calculates to
approximately 0.004 cases/100 (0.4/10,000) FS personnel /month.

## Conclusions and Recommendations

Tuberculosis, usually latent, is a common infection in persons serving
in the Foreign Service. Persons living in endemic areas should be tested
on an annual basis. This is important because the risk of active disease
is greatest in the first two years after skin test conversion. The
highest risk is in the first seven months after exposure (Figure 3). The
risk of active TB after exposure that results in a positive skin test is
estimated at 5% in the first two years after exposure in immunocompetent
persons and an additional five percent during the rest of the lifetime
(6). Persons who are immunocompromised have a much higher risk of TB
(Figure 3). Persons with underlying medical conditions such as diabetes,
chronic renal failure, head and neck cancer, organ transplantation and
injection drug use also have a higher incidence of active TB. Persons
with silicosis have a rate of active TB nearly as high as those with
HIV.

Treatment of latent TB with INH or Rifampin is highly effective in
reducing the incidence of active TB. Treatment of latent TB with 9
months of INH is more effective than 6 months of therapy in reducing the
risk of tuberculosis (3). The teenager reported above with suspected TB
was treated only 6 months. The combination of rifampin plus pyrazinamide
for two months, while attractive because of the short duration,
unexpectedly proved to be too toxic. This was a surprise since these two
drugs are commonly given as part of the four-drug combination used for
treating active TB. Presently, only INH for 9 months or rifampin for
four months are recommended treatments.

A common cause of confusion in testing with intradermal PPD is the BCG
vaccine. This live, bacterial vaccine is commonly given during the first
month of life in areas where TB is endemic. Studies of intradermal
testing with PPD after BCG vaccine indicate that infants given the
vaccine develop a reactive PPD skin test within 8 weeks. However, by 12
months, the PPD skin test is again negative. Therefore, infants
immunized with BCG should be tested at 12 months of age (7). A positive
reaction should be considered suggestive of exposure to TB and the
patient treated accordingly (3). When BCG is given later in life or when
multiple doses of BCG are given, the PPD may be positive up to 10 years
(7). The US Public Health does not recommend the use of BCG because the
results of studies indicate highly variable results of protection
against TB. Furthermore, BCG confuses the interpretation of PPD
intradermal testing.

Persons who are born in areas endemic for TB are often found to have
latent TB. Immigrants with latent TB have a rate of active TB similar to
the rates in the country of origin for the first five years after
immigration to the US (Figure 4) (3, 7-9). Therefore, the USPHS
recommends new immigrants with latent TB be treated. As a corollary,
persons of foreign birth who have latent TB who marry or are adopted in
the Foreign Service should also be treated.

One of the deficiencies revealed by review of reports of latent TB is
the frequent lack of the date of the last PPD skin test. This causes
difficulty in determining the duration of latent TB. Since the risk of
active TB is much higher in a recent convertor, this information is
important in discussing the benefits of therapy with the patient. Every
effort should be made to determine the result and date of the last PPD
skin test. Persons with latent TB who have been reactive for more than
two years may also benefit from therapy for latent TB because they have
a 5% lifetime risk of developing active TB, most likely after the age of
60. In addition to medical conditions mentioned above, increasing age
and the decreased immune response of older age increase the risk of
active TB as seen by the figure of the incidence of active TB in the US
(Figure 5). The increasing rate seen with increasing age is largely due
to reactivation of latent TB.

Monitoring of patients with latent TB is important. The most serious
side effects of INH include hepatitis and neuropathy. Rifampin can also
cause hepatitis. The USPHS recommends monthly [clinical]{.underline}
follow-up of patients on these two drugs. Monitoring of liver enzymes is
not ordinarily recommended unless the patient is at increased risk for
hepatitis such as pregnant or peripartum females, patients with liver
disease or those taking other hepatotoxic drugs, or patients with HIV.
Several patients were unnecessarily stopped on therapy because of mild
elevations of liver enzymes, even though the patient was feeling fine
and had no risks for hepatotoxicity. Persons with elevation of liver
enzymes [five]{.underline} times the upper limits of normals should stop
therapy. Monthly follow-up with a daily log of medications documents the
patient's progress in therapy and alerts the clinician to possible
toxicities. These monthly medication logs should be forwarded to MED for
inclusion in the patient's chart.

Treatment for occupationally-acquired latent or active TB is provided by
MED. INH medication cost \$18 for a 9-month treatment. Rifampin is
somewhat more expensive at approximately \$1.10 per day for 600 mg for
four months or approximately \$130, but the patient can request
reimbursement for this medication. Increased efforts should be made to
encourage completion of therapy. Completion of therapy should be marked
with a certificate of completion to the patient and the patient's chart.
Efforts should be intensified to quantitate the incidence of TB exposure
by Post by annual testing and complete reporting of monthly statistics.

Literature cited:

1\. CDC. World TB Day \-\-- March 24, 2002. MMWR 2002; 51:229

2.  Advisory Committee for the Elimination of Tuberculosis. A strategic
    plan for the elimination of tuberculosis in the United States. MMWR
    1989;38: (Suppl S-3)

3.  CDC. Targeted tuberculin testing and treatment of latent
    tuberculosis infection. MMWR2000; 49: (No. RR-6).

4.  CDC Fatal and severe hepatitis associated with rifampin and
    pyrazinamide for the treatment of latent tuberculosis infection --
    New York and Georgia, 2000. MMWR 2001; 50:289-291

5.  CDC. Update: Fatal and severe liver injuries associated with
    rifampin and pyrazinamide for latent tuberculosis infection, and
    revisions in American Thoracic Society/CDC recommendations -- United
    States, 2001.

6.  Small PM, Fujiwara, PI. Management of Tuberculosis in the United
    States. N Engl J Med 2001; 435:189-200.

7.  Lee E, Holzman, RS. Evolution and Current use of the Tuberculin
    Test. Clin Infect Dis 2002:34:365-370.

8.  McKenna, MT, MCray, E, Onorato I. The epidemiology of tuberculosis
    among foreign-born persons in the United States, 1986-1993. N Engl J
    Med 1995; 332:1071-6.

9.  CDC. Tuberculosis morbidity among U.S. --born and Foreign-born
    populations -- United States, 2000. MMWR 2002; 51: 101-104.