Bad Air, Bad Blood: A Homeric Admonition
by John S. Marr, MD, MPH, and Robert M. Maulitz, MD
Dr. John Marr had been the New York City health department’s principal epidemiologist for four months when in early October 1974 he received an unusual telephone call from the Brooklyn-Cumberland Medical Center. The physician caller reported a case of malaria, which by itself was neither urgent — the patient was doing well, nor unusual — except for the suspected source of the disease.
Malaria, a mosquito-borne disease had long disappeared from the city, but now it was being reported due to a transfusion of infected human blood, something that certainly had been documented, but was highly unusual.
Before the mosquito was incriminated as the natural vector of malaria, many theories attempted to explain malaria’s origin and environmental source. As implied by its name, malaria derives from the Italian mala (bad) and aria (air). It was an early close-but-no-cigar belief that the disease somehow emanated from miasmatic vapors drifting out of swamps and jungles.
Malaria is a primordial human affliction that arose as a “species-jump” from gorillas to humans tens of thousands of years ago. The parasite (Plasmodium) was spread by mosquitoes within primate populations and like many other zoonoses eventually jumped from mammals to humans.
Various non-primate Plasmodium species infect scores of mammals, as well as birds and reptiles. All are transmitted by the bite of the female of a particular genus of mosquito — Anopheles. Once the parasite is siphoned from its sufferer’s blood it enters the insect’s gut and undergoes sexual reproduction. Approximately two weeks later millions of progeny swarm throughout the insect and find their way to the salivary glands, ready to be injected in the next bite. But man-made technologies have been developed in the modern world allowing additional modes of spread through body piercing, tattooing, needle sharing, and transfusions.
The Brooklyn patient had been successfully treated, but the source of her infection was out of the hands of the doctor who had called Marr. The infected blood came from the hospital blood bank; the blood bank acquired it from the Red Cross blood center in Brooklyn; the Red Cross center received its units from many donation centers around the city. Marr told the physician that he would try to trace the ultimate source of infection, an unknown blood donor.
He decided to assign the investigation to the CDC’s Epidemiology Intelligence Service (EIS), officer, Bob Maulitz. Soft-spoken with a residual Alabama twang, the young man had blond hair and wore fashionable wire frame glasses. He had been in the bureau for more than a year. Marr remembered his first encounter a few months before when he introduced himself to the EIS officer and asked if he was enjoying his assignment. The answer was polite—things were quiet, he said, and he wasn’t being swamped by investigations. Marr asked if he could help him in any way. Bob shrugged but then asked if Marr could intervene on his behalf — he wished to use the only shower in the health department’s monolithic building. He explained that the shower was part of a deputy commissioner’s office suite and when he requested its use he was told that the shower was off-limits to him.
Marr was puzzled. It was a strange request. Didn’t Bob have one in his apartment? Bob then explained that he jogged to work each morning from the upper East Side—a five-mile jaunt
to prepare for the Boston marathon the following April. Marr admired his spunk and said he would enquire on his behalf, but since Marr was still a new kid on the block — he had not yet met the deputy commissioner — his intervention might have to wait.
Aside from Bob’s hygienic concern, he also stated that he wanted to investigate an outbreak but as of yet nothing had appeared on the radar screen. Gotham was quiet. He wished for a respiratory outbreak—flu—even TB—but the city had slept that fall.
The city was at its nadir point in 1974: it faced imminent economic default made memorable by the Daily News front page “Ford to City: Drop Dead.” Garbage strikes were routine; haggard bag people appeared from tunnels onto Park Avenue; addicts prowled alleys and camped out in abandoned buildings; apartment break-ins were routine; muggings had become commonplace; street protests were a part of daily life. The month before the two witnessed a remarkable march from the department’s windows when thousands of Chinese-Americans silently passed below from nearby Chinatown to City Hall protesting some grievance. In the Bronx arson and more violent protests were common. The neighborhood’s 41st precinct police station, dubbed Fort Apache by the media, was later re-named the Little House on the Prairie when surrounding buildings were razed.
The single case of transfusion-malaria did need investigation. The first step was to determine the background incidence of malaria in the city and country —how unusual was this case? In the early 1970s malaria was on the upswing throughout the United States, primarily due to returning Vietnam veterans and a change in immigration quotas that permitted people from African and Asian countries to apply for green cards. By the end of 1974, 300 cases of malaria had been reported nationwide: 24 (12%) were from New York City. All 24 cases had been investigated: All were in travelers or immigrants who had recently arrived from Asian and African locations. Over the previous five years, 181 mosquito-borne cases had been documented. The sources: 95 from exposure in Africa; 67 from Asia, and the remaining few from Caribbean and Latin American countries. There had been no transfusion-associated cases. At the time the two men did not know that the Brooklyn case—even though it was due to transfusion —was going to be different from any other malaria investigation in New York City’s history.
The patient had been born in the States and had not traveled outside the city; she obviously had to have been infected by the blood she had received, but not necessarily. They were not 100% sure and discussed three possibilities:
- An incorrect diagnosis. However, the diagnosis was confirmed by multiple blood smears and confirmed by a department tropical disease expert.
- A local mosquito bite. However, local transmission had ended by the turn of the century and Anopheles mosquitoes were not common in the city.
- A syringe shared with an infected drug addict. This was also most unlikely; the patient was a 78- year-old housewife.
The transfusion. It was the most likely explanation. In August, the woman received 14 units of whole blood and packed red cells during an operation. In late September, while still in the hospital, malaria parasites were noted in a routine blood smear.
Marr and Maulitz wondered whether this was a rare occurrence, and checked further back into the bureau’s records and CDC statistics. Over the last few years only one case of transfusion-associated malaria had been reported in the entire United States. The one case in Brooklyn was indeed unusual.
Malaria has a complex life cycle: sexual replication occurs in the mosquito; an asexual cycle occurs in humans. Once injected by the mosquito, the parasites enter and asexually multiply within red blood cells until the cells burst, releasing a spawn of millions of new potential infectious agents that re-infect other red blood cells. A periodic cycle of new red cell bursts occurs every few days causing the signature presentation of periodic bouts of fever, rigor and profuse sweating. Toxic detritus spills into the bloodstream causing sludge within blood vessels, leading to stroke, heart attack, and multi-organ failure.
The severest form—so-called black water fever—produces molasses colored urine as millions of red cell remnants clog the kidneys. (Eight years before in an African missionary hospital, Marr had witnessed the dreaded Coca Cola-like urine expelled in a tiny stream just before a baby died in his arms.) He knew that malaria in any form and at any age was a serious disease. Transfusion-acquired malaria was not just a complication; it could tip the balance in a patient who had required a transfusion. An isolated case—even if mild—also presented another larger public health threat: the unknown donor was still at large.
Marr and Maulitz knew that tracking down the 14 donors matching the 14 units of blood the patient had received was going to be time consuming. They arranged to get donor-identifying information from the Red Cross. They planned to identify suspects by telephone or mail. Based on clues of previous possible malaria exposures, they hoped to draw blood from a smaller list of most likely cases. The blood would be screened for antibodies to malaria – presumptive evidence of a previous infection. Examining a single blood smear would take hours since only one in 50 million red blood cells might be infected. A special serological test detected malaria antibodies when a blood smear would be considered negative. No one should have a positive response unless he harbored a past or present infection.
The investigation became more intriguing the following week when the curious single Brooklyn case turned into an “epidemic.” A second transfusion case was reported. (An epidemic is an excess number of cases of any disease; the number of cases needed to qualify as an epidemic is fluid based on previous experience. A hundred cases of flu in the city during the winter was not epidemic, it is considered ”endemic”—i.e. the usual amount of cases, but a single case of a new flu strain would be considered epidemic since it exceeded past experience.) One case of transfusion- associated malaria was a happenstance event, but two cases within a week in the city was an “epidemic.” Since no other states reported other transfusion cases, something truly unique was occurring in New York City.
The second transfusion case was reported from the Sloan Kettering Memorial Medical Center in Manhattan. In August, a patient had received 64 units of blood during extensive surgery followed by two post-operative episodes of bleeding. Her subsequent course went well and she was eventually discharged in early September. By mid-month she began to experience recurrent fevers unresponsive to antibiotics and she was readmitted. A routine blood smear revealed P. malariae parasites. When Marr and Maulitz were informed of the second case within a week of the first— both due to P. malariae— they suspected that the two had to be connected by a “common source.” But what was that common source?
They began by reviewing background records of malaria cases in the city using the standard epidemiologic procedure of time, place and person. In the previous 15 years there had been 267 cases in the city. Most were in men and 12 percent in women. Only seven percent were due to P. malariae. The last case of malariae had been in 1972: also from a transfusion. An unsettling thought was that the 1972 transfusion case was due to a silent chronic- disease -carrier who does not realize that he/she can transmit an infection (like Typhoid Mary) and might be responsible for the two new cases. They immediately checked the report and found that the 1972 donor had been identified and this hypothesis was eliminated.
Another thought occurred that a single person—a “professional donor”—might have sold blood twice in different Brooklyn locations. A quick check of names and addresses did not match, but it was not inconceivable that a financially strapped professional donor or “pro” might have sold blood under different names. In the 1970s most donors were “Bowery bums,” selling a pint to buy a pint of muscatel; other pros were drug addicts who sold their blood for a “fix.” For-profit blood banks were common in rundown neighborhoods, where one could see scraggy men on littered streets slouching in lines to sell their blood. Their blood would later be sold to high-end hospitals where “truth in labeling” was absent — the blood’s provenance remained a mystery to doctors and their patients. But a common donor as the common source was eliminated when the two transfusion recipients where shown to have different blood types.
Another intriguing clue was that the species of malaria in both cases was P. malariae. Malaria can be caused by three other species: P. falciparum (aka malignant tertian), the deadliest of all four with fever spikes occurring every third day; P. vivax (aka benign tertian), produces fever spikes every 48 hours); P. ovale, (another benign tertian form, the rarest of the four). P. malariae, (aka benign quartan) malaria produces mild symptoms every fourth day) and after years becomes quiescent. Finding this species was consistent to what was known about transfusion-associated malaria. P. malariae had been shown to be responsible for most cases of transfusion-associated malaria, as well as cases acquired through needle sharing. By its very benign nature P. malariae does not cause much, if any symptoms in its carrier—the parasites slowly multiply in red blood cells for decades, attenuated by the immune system; eventually becoming symptomless. Because of its mild nature P. malariae was also the most common cause of congenital malaria (actually con-natal) acquired during birth when an asymptomatic mother’s blood mixes with her baby’s.
But like the newborn, recipients of transfused malaria lack antibodies from previous exposure; the uninvited guest is perceived as a new infection. A few weeks after silently incubating and multiplying, it causes classic symptoms of fever-chills-sweats and anemia that would complicate a serious illness requiring a transfusion. During the Vietnam War most transfusion cases reported were due to vivax and falciparum. Both can be rapidly fatal if diagnosis is delayed. Fatalities in military hospitals were much lower than in civilian hospitals since malaria was immediately considered as the cause of unexplained fever. Even though the diagnoses in the two transfusion cases may have been delayed, they were mild and due to P. malariae.
In the 1970s there was no routine serological screening test for malaria prior to donation; the disease was so uncommon that it did not justify testing 50 million units of blood to find one positive result. At the time routine serological tests on donor blood were limited to syphilis. But even the most disreputable blood banks were required to provide identifying records on donors. The two epidemiologists had information on the 14 names from the first case and 64 from the second case: name, age, address, and telephone number. They theorized that the two donors probably lived in the city since most blood was collected from local blood banks and hospitals. They knew they had to contact all of them, but trying to contact them by telephone might not be productive. They devised a letter explaining that the blood donors might be unsuspecting carriers, and asked the donors to fill out a questionnaire about their general health and travel history; then sent the covering letter and questionnaire and waited for replies.
By mid-November they had received a surprisingly large number of responses. Half of Case 1’s fourteen donors had completed answers to their general health, history of unexplained fevers, birthplace, occupation, military service and foreign travel. Thirty-eight Case 2 donors also responded. They debated what to do with the incomplete results (Seven for Case 1; twenty-six for Case 2). A second mailing was sent out in early December, implying that a response was required by the Department of Health, although there was no authority to do anything if the donors failed to answer. The vaguely intimidating questionnaire resulted in a few more responses. By early December they still had not received enough responses to initiate serological testing. Even if the non-responders were to receive a third hand-addressed letter from the health department, they probably would have trashed it like they probably had done with the previous two.
It was winter and the weather was bleak. Bob stopped jogging. Marr discovered that the deputy commissioner never used his shower—he never even knew it existed. His secretary had vetoed Bob’s earlier request since the shower was being used as a storage area. It seemed like the two had wasted their time in thankless pursuit.
Enter a deus ex machina disguised as Mike Sudwertz, a fourth year medical student from New York Medical College. Mike had been disciplined by the school’s department of preventive medicine chairman for a minor indiscretion two years before. His belated penalty was that he had to spend his precious fourth year elective in an exposure to preventive medicine and his professor assigned him to work at the health department. Marr reluctantly accepted the responsibility of mentoring the student for a month although he had some empathy for the kid—10 years before he had also been a wiseacre student at the same medical school and same class when the same professor tried to tell the class about something new called Medicare.
Mike was a chunky guy with a mop of thick black hair and a twinkle of mischief in his eye. A cheerful fellow, he was not at all resentful of the loss of his precious elective month. Marr had no idea what to do with him during his first week, but he showed some mettle by getting up at four in the morning to accompany a health inspector to the Fulton Fish Market to smell fish. To Marr, that showed commitment. Maulitz and Marr decided to share their malaria conundrum with him since they had run out of ideas.
Mike was intrigued and immediately volunteered to assist. He was a noodge in the good sense of the word. He took the list of non-responders home with him and called each one in the evenings repeatedly until he got answers to the questionnaire. Once a donor was on the phone, some apologized for not responding to the letters and all were eager to comply. Within two weeks he had completed three additional donors for Case 1 and all the donors from Case 2 had now responded The three realized that the remaining four Case 1 donors would probably never be found: two pints had come from Europe, the other two never seemed to be at home or answer their telephones.
The next step was to perform serological blood tests on the donors. The CDC was ready to carry out testing but the large number was unwieldy. Home visits to draw blood would take time, and the lists needed to be whittled down. Since all 64 donors in Case 2 had responded they decided to focus on them first—one of them had to be the infected donor. Risk profiles were created: High, Middle and Low. High Risk donors were those who had been born in or traveled to countries with high levels of malaria; Middle Risk donors were those who had been born in or traveled to previously infected countries or areas such as the Caribbean; Low Risk donors were those who had been born in the United States and had never traveled abroad.
Bob and Mike went to Brooklyn to draw blood specimens from all the 30 High Risk donors. By the end of January they finally received the results—all 30 serologies were negative. In frustration, Bob began jogging through the snow and Mike returned to medical school. Marr thought a second round might be the last effort they would make, and then they would have to discontinue the investigation.
Since the Low Risk group did not appear likely—no one who has always lived in the U.S. gets malaria — they excluded them and banked on the Middle Risk group. These 17 admitted to having visited an endemic country sometime in the past five years or were raised in a country that had once been endemic for malaria. Bob made arrangements for another round of testing. Another month passed; it was mid-February when they got the results back from the CDC.
Eureka! is a Greek expression everyone knows. Archimedes shouted it when he discovered how to measure the volume of an irregular object. The Eureka moment came when a single person came back with a high titer to P. malariae. Supporting the Archimedes moment, the donor was a Greek-American woman. Bob called the home and talked to the woman’s son and arranged to visit the next day. The interview was difficult since she spoke only Greek, but her son acted as translator. The story was fascinating and confirmed knowledge about chronic P. malariae infections. She was a 53-year-old housewife who had lived in Brooklyn for 31 years. She had been born in Sparta, Greece in 1921 and immigrated to the United States in 1952. When questioned about malaria, she recalled that at age of six she had been treated for a “fever” with quinine, but did not know whether the fever was due to malaria. Quinine was the only drug of choice for malaria at the time. She probably had malaria. She also said that she had never returned to Greece since immigrating, nor had she traveled outside the United States since then. She was asked if she had donated blood prior to her contribution the previous September. She answered it had been her first time. But why, Bob wondered, had she chosen to donate blood for the first time at her age? She explained that a priest at her Greek Orthodox Church, at the request of the local Red Cross, had asked for donations to assist efforts during the ongoing conflict between the Greek and Turkish armies in Crete.
Case 1 was a challenge. There were 10 of 14 completed questionnaires, but four were outstanding and would probably remain so. Then one frigid morning, one of four suddenly appeared in Marr’s office. He had been traveling for the past few months, and upon returning to Manhattan had opened the two letters. He recognized Marr’s name—they had been classmates in college, although Marr didn’t remember him. He said he had been in the army in Vietnam until discharge, then bummed around Southeast Asia, picking up some interesting infections, but to his knowledge not malaria. His blood was sent it immediately to the CDC; a week later it came back negative.
Marr and Maulitz were now left with a single unknown American donor and two European donors who were certainly out of reach. Of the 10 known donors three had somewhat suggestive histories of malaria exposure and were labeled as High Risk; five others had insignificant exposure histories and were considered the Middle Risk; and two remaining with no possible exposure—the Low Risks. The names of the High+Middle Risk donors were folded together. Perhaps there was some overlooked clue, some arcane piece of information, contained in a donor’s name, age, occupation, travel history, or residence. Nothing stood out, and they decided to test the three High Risk donors.
The first candidate was a native of Dutch Guyana who had lived in the city for decades; his test proved negative. The second was a merchant seaman who had traveled to numerous South American ports; he also tested negative. The third man was a geology professor living in New Jersey. The men had to wait a few days for the New Jersey Health Department to collect his blood. The New Jersey epidemiologist contacted the professor, who agreed to have his blood drawn, and then sent it to the CDC. If the man turned out negative, the investigation was down to seven very unlikely Middle-Low donors.
As they waited for the results on the third donor, Marr looked at the answers on his questionnaire: name, age, occupation, place of birth, and travel history. And there it was right in front of him! He had missed the connection. He had another Eureka moment. He knew it was going to be the professor. He knew it, he knew it, he knew it. The man’s last name was Greek and he had been born in Cyprus.
They now waited to hear from the New Jersey epidemiologist and the CDC. A telephone call in March first came from Atlanta. The New Jersey man’s serology was positive for P. malariae at a titer of 1:1,024 — which was quite high. Marr called the college where he taught and got him on the line. After explaining that he had malaria in his blood and it could easily be treated, he was asked additional questions. He said he had been born in a small village in Cyprus in 1936. After college he had immigrated to the United States in 1959, and had taught geology for the last 15 years. He said that he had briefly returned to Cyprus see his family in 1963, 1967 and 1970. During the trips he denied having malaria or unexplained fevers. The man’s only previous blood donation was in 1953 for an ailing mother in Greece, and he had never donated again until the previous fall when he had traveled to the city.
Everything began to make sense: Before World War II five European countries were endemic for malaria; Greece had been the last country to eradicate the disease. During that time transfusion-induced malaria had been common in Greek children since their parents were required to be donors.
There was one last question for the professor: Why had he, as a long-term citizen of New Jersey, chosen to donate blood in New York? He said that he and a friend visited a Greek Cypriot social club in Queens the previous year. His friend persuaded him to donate blood because of the conflict in Cyprus. The plea came from a Brooklyn priest in the Greek Orthodox Church.
Maulitz and Marr were ecstatic. Marr called Sudwertz and told him; he was also overwhelmed. Marr also telephoned the preventive medicine professor and praised Mike’s work. Bob called his boss in Atlanta, who told him to publish the results. A summary was sent to the New York City health commissioner, who was pleased. Marr remembered that a local TV science reporter, Frank Field, had visited the health department a few months before asking if anyone with a good story favorable to the department they should contact him. He decided to make the call and Field listened to him recounting the results of the investigation. The reporter said he would get back to him in a few days.
When Field finally called back, Marr was disappointed. Field pointed out that the findings had potential negative ramifications. The church’s request for donors would be publically identified as the “common source:” the media might demand to know who the Brooklyn woman and New Jersey professor were; a minority ethnic community might be unfairly stigmatized; patients in need of blood might be reluctant to accept a transfusion. Potential donors might also be reluctant to donate blood—inexplicably—since they believed they could acquire malaria from their gift.
Dr. Field convinced the men not to publicize the finding. His admonition was followed. A month later Maulitz placed # 977 in the Boston Marathon (3 hours, 2 minutes, 52 seconds). In June, Sudwertz graduated from New York Medical College and received an A in Public Health. A year later the findings were published in a tropical disease journal without incident. The incident of the Brooklyn donor-carrier would be the longest documented case between a previous malaria infection and subsequent transmission. She bested the previous record by one year.
Another admonition seemed to be an appropriate ending to the investigation — the warning about Greeks bearing gifts.
- This case reports on two cases of malaria in individuals who received blood transfusions. This is referred to as an “epidemic”. Is epidemic the correct descriptive term? Comment on why or why not.
- All blood is tested for evidence of certain infectious disease pathogens. Please name four of these?
- The case describes that local transmission had ended by the turn of the century in New York City and Anopheles mosquitoes were not common in the city. Are these mosquitoes present in other regions of the U.S. Has there ever been local transmission of malaria in these regions?
ABOUT THE AUTHORS
John S. Marr, MD, MPH, is the former State Epidemiologist for the Virginia State Department of Health. At the time of this case, he served as the Director of the Bureau of Communicable Disease for the New York City Department of Health.
Robert M. Maulitz, MD, is an Associate Professor in the Department of Medicine at National Jewish South Denver. At the time of this case, he was the Epidemic Intelligence Service Officer (EIS) for the Centers for Disease Control and Prevention.
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